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WO2018013483A1 - Peptides bloquant le canal kv1.3 et utilisations de ces derniers - Google Patents

Peptides bloquant le canal kv1.3 et utilisations de ces derniers Download PDF

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Publication number
WO2018013483A1
WO2018013483A1 PCT/US2017/041376 US2017041376W WO2018013483A1 WO 2018013483 A1 WO2018013483 A1 WO 2018013483A1 US 2017041376 W US2017041376 W US 2017041376W WO 2018013483 A1 WO2018013483 A1 WO 2018013483A1
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WIPO (PCT)
Prior art keywords
kvl
seq
inhibitor
antibody
binds
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Ceased
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PCT/US2017/041376
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English (en)
Inventor
Feng Wang
Changming Fang
Rongsheng E. Wang
Ying Wang
Peter G. Schultz
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California Institute for Biomedical Research
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California Institute for Biomedical Research
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Publication of WO2018013483A1 publication Critical patent/WO2018013483A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • C07K14/43513—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae
    • C07K14/43522—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae from scorpions
    • C07K16/11—
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2318/00—Antibody mimetics or scaffolds
    • C07K2318/10—Immunoglobulin or domain(s) thereof as scaffolds for inserted non-Ig peptide sequences, e.g. for vaccination purposes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin

Definitions

  • autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes mellitus, rheumatoid arthritis (RA), and psoriasis.
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • psoriasis psoriasis.
  • drugs such as steroids, FK 06, and cyclosporine often leads to severe side effects including opportunistic infections.
  • T EM effector memory T
  • T CM central memory T
  • Kvl .3 inhibitor molecules comprising a peptide inhibitor of Kvl .3, including antibody fusions comprising the Kvl.3 inhibitor connected to an antibody sequence.
  • Various antibody fusions disclosed have similar in vitro biological activities on suppression of T EM cell activation as their Kvl .3 peptide inhibitor components, but with longer plasma half-lives. Such increase in half-life may provide for reduced injection frequency and increased compliance in clinical use. In some cases, the plasma half-life of fusion proteins is about, 10-, 20-, 50-, or 100-fold longer than corresponding peptide K l .3 peptide inhibitors alone.
  • various antibody fusions have been generated to reduce antigen binding. For instance, antibody fusions are provided using a palivizumab scaffold where RSV binding is reduced or eliminated.
  • polypeptide comprising SEQ ID NO: 36:
  • Zl, Z2, Z3, Z4, Z5, Z6, Z7, and Z8 are independently selected from C, A, G, S, I, and L;
  • X I is selected from S and K;
  • ⁇ 2 is selected from S and P;
  • ⁇ 3 is selected from P and K;
  • ⁇ 4 is selected from P and L;
  • ⁇ 5 is selected from K and P;
  • ⁇ 6 is selected from R and G;
  • ⁇ 7 is no amino acid or T
  • ⁇ 8 is selected from K and P;
  • ⁇ 9 is selected from N and Y;
  • ⁇ 10 is selected from Y and N;
  • X I I is selected from Y, R, F, and G;
  • the polypeptide does not comprise the following combination of amino acids: Zl is C, Z2 is C, Z3 is C, Z4 is C, Z5 is C, Z6 is C, Z7 is C, Z8 is C, XI is S, X2 is S, X3 is P, X4 is P, X5 is K, X6 is R, ⁇ 7 is no ammo acid, X8 is K, X9 is N, X10 is Y, and XI 1 is Y.
  • Z 1 is C
  • Z2 is C
  • Z3 is C
  • Z4 is C
  • Z5 is C
  • Z6 is C
  • Z7 is C
  • Z8 is C
  • XI is K
  • X2 is P
  • X3 is K
  • X4 is L
  • X5 is P
  • X6 is G
  • X7 is T
  • X8 is P
  • X9 is Y
  • X10 is N
  • XI 1 is selected from R, F, and G, or (xii) any combination of (i) - (xi).
  • the polypeptide comprises a sequence selected from SEQ ID NOS: 37-63.
  • composition comprising the polypeptide.
  • the composition comprises an antibody or antibody fragment connected to the polypeptide.
  • the antibody fragment comprises at least one, at least two, or at least three CDRs of an antibody light chain and/or heavy chain; wherein optionally one or more of the at least one, two, or three CDRs has been modified to reduce antigen binding
  • the antibody or antibody fragment comprises one or more sequences selected from SEQ ID NOS: 21-32 and 101-130.
  • the polypeptide is positioned within the antibody or antibody fragment. In some embodiments, at least about 10, 20, 30, 40 or 50 contiguous amino acids of the antibody or antibody fragment are positioned N-terminal to the polypeptide, and at least about 10, 20, 30, 40 or 50 contiguous amino acids of the antibody or antibody fragment are positioned C-terminal to the polypeptide.
  • composition comprising an antibody region modified by insertion of the polypeptide into the antibody region; wherein the unmodified antibody region comprises a first CDR, a second CDR, and a third CDR, and the modification comprises: (a) positioning the polypeptide (i) between two amino acids of the first CDR, (ii) between an amino acid of the antibody region and the first amino acid of the first CDR, (iii) between an amino acid of the antibody region and the last amino acid of the first CDR; or (b) replacing at least one amino acid of the first CDR with the polypeptide.
  • the first CDR of the unmodified antibody region is selected from: a CDR1 of an antibody light chain, a CDR2 of an antibody light chain, a CDR3 of an antibody light chain, a CDR1 of an antibody heavy chain, a CDR2 of an antibody heavy chain, and a CDR3 of an antibody heavy chain.
  • the first CDR of the unmodified antibody region is selected from SEQ ID NOS: 21-32 and 101-123.
  • the antibody region comprises: (1) a heavy chain of an antibody variable domain, (2) a light chain of an antibody variable domain; (3) at least about 10, 20, 30, 40 or 50 contiguous amino acids; or (4) any combination of (1)- (4).
  • the polypeptide is connected to the antibody region by one or more linkers and/or extension peptides. In some embodiments, the polypeptide is inserted into the antibody region in an insert region comprising a first extension peptide, the polypeptide, and a second extension peptide. In some embodiments, the first extension peptide and the second extension peptide each form a helical secondary structure.
  • a method of binding a channel selected from: Kvl . l, Kvl .2, Kvl.3, Kvl.4, Kvl.5, Kvl .6, Kvl.7, Kv2.1, Kv3.1, Kv3.2, Kvl l . l, Kcl .
  • the method comprising combining the polypeptide of any of claims 1-17 with the channel; wherein if the channel is in an in vitro solution, combining comprises combining the channel and the polypeptide in the in vitro solution; and wherein if the channel is located in a subject, the method comprises administering the polypeptide to the subject.
  • a method of treating a subject comprising a disease or condition comprising administering to the subject the polypeptide.
  • the disease is an autoimmune disease or condition thereof.
  • composition comprising an antibody region first modified by insertion of a therapeutic polypeptide into the antibody region; wherein the unmodified antibody region comprises a first CDR, a second CDR, and a third CDR; and wherein the first CDR, the second CDR, the third CDR, or a combination thereof, has been further modified to reduce or eliminate antigen binding.
  • composition of claim 21, wherein the first modification comprises (a) positioning the therapeutic polypeptide (i) between two amino acids of the first CDR, (ii) between an amino acid of the antibody region and the first amino acid of the first CDR, (iii) between an amino acid of the antibody region and the last amino acid of the first CDR; or (b) replacing at least one amino acid of the first CDR with the therapeutic polypeptide; and wherein the modified antibody region comprises at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids.
  • the therapeutic peptide is a peptide inhibitor of a voltage-gated channel.
  • the first CDR of the unmodified antibody region is selected from: a CDRl of an antibody light chain, a CDR2 of an antibody light chain, a CDR3 of an antibody light chain, a CDRl of an antibody heavy chain, a CDR2 of an antibody heavy chain, and a CDR3 of an antibody heavy chain.
  • the first CDR is selected from SEQ ID NOS: 21-32 and 101-123.
  • the first CDR comprises the sequence "FGG.”
  • the antibody region is modified from a heavy chain variable domain of a palivizumab antibody having SEQ ID NO: 2, and the composition exhibits reduced binding to RSV-F as compared to the palivizumab antibody having SEQ ID NO: 2.
  • the antibody region is modified from a light chain variable domain of a palivizumab antibody having SEQ ID NO: 1, and the composition exhibits reduced binding to RSV-F as compared to the palivizumab antibody having SEQ ID NO: 1.
  • the composition comprises SEQ ID NO: 101: SMITX(i)X(ii)X(iii)FDV, wherein X(i) is selected from F, A, G, and P, X(ii) is selected from G, A, S, T, and P; and X(iii) is selected from G, A, V, L, and P.
  • FIG. 1 shows an exemplary design of humanized anti-Kv 1.3 antibodies.
  • Solution NMR structures of Toxin B (PDB ID: 2KIR) and Toxin A peptides (PDB ID: 2K90) are shown with the corresponding sequences (disulfide bonds are indicated).
  • Peptides were grafted into CDR3L and CDR2H of Synagis antibody (Fab fragment X-ray crystal structure depicted, PDB ID: 2HWZ), or into CDR3H (red) of BVK antibody (Fab fragment depicted, PDB ID: 1BVK).
  • FIGS. 2(A-B) show in vivo pharmacological performance of Syn-Toxin A-CDR3L (SEQ ID NOS: 7, 3).
  • FIG. 2A shows pharmacokinetics at a single dose of 2 mg kg, via subcutaneous injection.
  • FIG. 2B shows the pharmacokinetic profile of Syn-Toxin A-CDR3L in rat by i.v. injection.
  • Samples were analyzed by sandwich ELISA based on its binding to Kvl.3-overexpressing CHO cells. The estimated terminal half-life is 54. Oh.
  • IX day of challenge
  • 2X 2X
  • Syn-Toxin A-CDR3L was injected with a single dose 24h ahead of challenge (IX), or one dose/day 48h ahead of challenge (2X). Shown are the ear thickness differences between left and right ear 24 h after ovalbumin challenge.
  • Kvl .3 inhibitors and compositions comprising Kvl .3 inhibitors.
  • Exemplary compositions are antibody fusions comprising a Kvl .3 inhibitor connected to an antibody or antibody fragment, e.g., via one or more extension peptides and/or linker peptides. In some cases, the antibody or antibody fragment has been modified to reduce or eliminate antigen binding.
  • such antigen binding modification may be made at one or more CDRs different from the CDR in which the Kvl .3 peptide inhibitor is fused, or the same CDR in which the Kvl .3 peptide inhibitor is positioned.
  • Kvl .3 inhibitors and Kvl .3 inhibitor antibody fusions described herein selectively suppress effector memory T (T EM ) cell activation while having improved half-lives over the Kvl .3 peptide inhibitor alone.
  • T EM effector memory T
  • various fusion antibodies provided have shown improved plasma half-life and serum stability in rodents compared to Kvl .3 peptide inhibitor alone. Accordingly, Kvl .3 inhibitor antibody fusions described herein may provide selective immunosuppression for the treatment of autoimmune diseases.
  • Kvl .3 inhibitors provided herein, and compositions thereof, include those having SEQ ID NOS: 12- 15, 131, and 36-63.
  • the Kvl .3 inhibitor comprises SEQ ID NO: 36
  • each of X l-Xl l and Z 1-Z8 may be any natural or unnatural amino acid, or may indicate absence of an amino acid.
  • XI is S or K
  • X2 is S or P
  • X3 is P or K
  • X4 is P or L
  • X5 is K or P
  • X6 is R or G
  • X7 is T or indicates no amino acid present at this position
  • X8 is K or P
  • X9 is N or Y
  • X10 is Y or N
  • XI 1 is Y, R, F or G
  • Zl is C, A, G, S, I, or L
  • Z2 is C, A, G, S, I, or L
  • Z3 is C, A, G, S, I, or L
  • Z4 is C, A, G, S, I, or L
  • Z5 is C, A, G, S, I, or L
  • Z6 is C, A, G, S, I, or L
  • Z7 is C, A, G, S, I, or L
  • Z8 is C, A, G, S, I, or L.
  • a Kvl .3 inhibitor antibody fusion comprises a Kvl .3 inhibitor connected via one or more extension and/or linker peptides to, or otherwise positioned within, a CDR of an antibody or antibody fragment.
  • the Kvl .3 inhibitor may be positioned within the antibody such that at least 10 amino acids of the antibody are N-terminal to the Kvl .3 inhibitor and at least 10 amino acids of the antibody are C-terminal to the Kvl .3 inhibitor.
  • the Kvl .3 inhibitor may be selected from SEQ ID NOS: 12-15, 131, and 36-63.
  • T is a therapeutic peptide comprising a Kvl .3 peptide inhibitor
  • L is a linker peptide
  • A is an antibody or fragment thereof (e.g. , variable domain)
  • E is an extension peptide.
  • An antibody fusion described herein may comprise one or more polypeptide chains having any one of Formulas I- IV. ErL i -T-L j -E ⁇ A
  • the antibody or antibody fragment A may comprise or be derived from a heavy chain or a light chain variable domain, where an insert portion comprises any one of therapeutic peptide T, extension peptide E, and linker L is fused to a CDR of the variable domain, with optional replacement of one or more of the CDR amino acids.
  • the CDR may be CDRIH, CDR2H, CDR3H, CDRIL, CDR2L or CDR3L. In some cases, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids of the CDR of the antibody A are replaced with the insert portion.
  • the insert portion may comprise, and/or be connected to the antibody A via one or more linkers.
  • a linker is positioned between A and El and/or between E2 and A in any of Formulas I-IV. Additional modifications to the vanable domain may be made to reduce or eliminate antigen binding.
  • Antibody fusions comprising a Kvl .3 peptide inhibitor may be used to treat a disease or condition in a subject in need thereof.
  • a method of treatment comprises administering to the subject a composition comprising the Kvl .3 inhibitor, e.g., an antibody fusion.
  • the antibody fusion comprises a first antibody chain having the formula of I, II, III, IV, or any modification, portions, or additions thereof; and an optional second antibody chain.
  • the second antibody chain may or may not be an antibody fusion.
  • the subject may be one comprising an autoimmune disease, having or expecting to have an organ transplant, or one having an affliction related thereto.
  • connection of an antibody or antibody fragment to a Kvl .3 peptide inhibitor as described herein has an effect of increasing half-life or otherwise improving delivery of the Kvl.3 peptide inhibitor.
  • the half-life of the Kvl .3 peptide inhibitor is improved by at least 10-, 20-, 30-, 40-, 50-, 60-, 70-, 80-, 90-, 100-, or 150-fold.
  • the Kvl .3 peptide inhibitor and antibody are recombinantly produced from a genetic construct, and then expressed in vitro using cell culture techniques.
  • a construct encoding a Kvl.3 peptide inhibitor connected to a CDR of a first antibody is co-expressed with a second construct comprising a second antibody, to produce a recombinant Kvl .3 inhibitor antibody fusion protein.
  • the first antibody may comprise a heavy chain or portion thereof
  • the second antibody may comprise a light chain or portion thereof, or vice versa.
  • Such first and second antibodies may be expressed and then connected via disulfide bond, or in other instances, the antibodies are produced together from a single construct, e.g., to produce a scFv.
  • Genetic fusion constructs may also comprise one or more extension peptides, linker peptides and/or proteolytic cleavage sites.
  • a Kvl .3 inhibitor antibody fusion comprising a Kvl .3 inhibitor connected to an antibody at the CDR position.
  • the Kvl .3 inhibitor need not be connected directly to the antibody, and may be connected via one or more extension peptides and/or linker peptides.
  • the Kvl.3 inhibitor is positioned within the CDR (sometimes referred to as a CDR fusion), which includes: the Kvl.3 inhibitor is positioned between two amino acids of the CDR, the Kvl .3 inhibitor is positioned between the antibody and the first amino acid of the CDR, the Kvl .3 inhibitor is positioned between the antibody and the last amino acid of the CDR, and/or the Kvl .3 inhibitor replaces a portion or all of the CDR and thus is positioned where the CDR previously existed.
  • the CDR fusion comprises a first antibody portion, the Kvl .3 inhibitor, and a second antibody portion.
  • the first antibody portion comprises one or more framework regions and, if applicable, any other CDRs N- terminal to the CDR where the Kvl .3 inhibitor is positioned
  • the second antibody portion comprises one or more framework regions and/or Fc regions, and if applicable, any other CDRs C-terminal the CDR where the Kvl.3 inhibitor is positioned.
  • Each of the first and second antibody portions may independently have a length selected from: at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, or at least about 50 amino acids.
  • positioned within the CDR indicates that no amino acids of the CDR are deleted.
  • positioned within the CDR indicates that at least 1, 2, 3, 4, 5, 6, 7, 8 or the entire CDR is replaced by the Kvl.3 inhibitor.
  • the Kvl .3 inhibitor is part of an insert portion that is positioned withm the CDR of the antibody.
  • the insert portion may comprise one or more extension peptides and/or linker peptides.
  • inserted does not necessarily limit the antibody fusions to those generated by modifying the DNA encoding the antibody by insertion of the DNA encoding for the Kvl .3 inhibitor, but may also or alternatively indicate that the DNA encoding the antibody and Kvl .3 inhibitor is de novo synthesized.
  • Exemplary Kvl .3 peptide inhibitors of the antibody fusions described include Toxin A (SEQ ID NO: 13), Toxin B (SEQ ID NO: 15), Toxin XX (SEQ ID NO: 36), Toxins C-Z and Toxins AA-CC (SEQ ID NOS: 37-63), and Stichodactyla toxin (ShK, SEQ ID NO: 131,
  • the Kvl .3 inhibitor may be part of an insert portion that replaces one or more amino acids of the CDR. In other cases, the insert portion is connected to the CDR, without CDR amino acid removal.
  • the insert portion comprises the Kvl .3 inhibitor and optionally one or more extension peptides and/or linker peptides. In some cases, one extension peptide is upstream of the Kvl .3 inhibitor sequence and a second extension peptide is downstream of the Kvl .3 inhibitor sequence.
  • the two extension peptides may form a coiled-coil or a beta-sheet.
  • a linker peptide connects on either side of an extension peptide.
  • a linker is present between antibody sequence and extension peptide sequence, and/or between extension peptide sequence and Kvl .3 peptide inhibitor sequence.
  • a Kvl .3 inhibitor antibody fusion has Formula I, Formula ⁇ , Formula III, or Formula IV.
  • an antibody portion of a Kvl .3 inhibitor antibody fusion refers to an amino acid sequence of an antibody, where "antibody” includes antibody and fragments thereof.
  • the antibody may comprise a heavy chain sequence, a light chain sequence, both a heavy chain sequence and a light chain sequence, or any portion or combination thereof.
  • the antibody portion of a fusion comprises a variable domain modified at one or more CDRs with a Kvl .3 peptide inhibitor.
  • Modification of a CDR includes the following configurations: the Kvl .3 inhibitor is positioned between two amino acids of the CDR, the Kv 1.3 inhibitor is positioned between the antibody and the first amino acid of the CDR, the Kv 1.3 inhibitor is positioned between the antibody and the last amino acid of the CDR, and/or the Kvl.3 inhibitor replaces a portion or all of the CDR and thus is positioned where the CDR previously existed. In some cases, the variable domain has been modified to reduce or eliminate antigen binding.
  • the antibody portion of a Kvl.3 inhibitor antibody fusion described herein may be any portion or fragment of an antibody.
  • an antibody is chimeric, engineered, recombinant, and/or humanized.
  • the antibody portion of Kvl.3 inhibitor antibody fusion may comprise an entire antibody molecule or any polypeptide comprising fragment of an antibody including, but not limited to: heavy chain, light chain, variable domain, antigen binding domain, constant domain, complementarity determining region (CDR), framework region, single domain antibody, fragment antigen binding (Fab) region, Fab', F(ab')2, F(ab')3, Fab', fragment crystallizable (Fc) region, single chain variable fragment (scFV), di-scFv, single domain antibody, trifunctional antibody, chemically linked F(ab')2, and any portion or combination thereof.
  • an antibody heavy chain comprises an entire heavy chain or a portion of a heavy chain.
  • a variable domain or region thereof derived from a heavy chain may be referred to as a heavy chain or a region of a heavy chain.
  • an antibody light chain comprises an entire light chain or a portion of a light chain.
  • a variable domain or region thereof derived from a light chain may be referred to as a light chain or a region of a light chain.
  • the antibody portion may be bispecific or trispecific.
  • a single domain antibody includes, but is not limited to, a single monomeric variable antibody domain.
  • an antibody portion of a Kvl .3 inhibitor antibody may be mammalian, human engineered or fully human, bovine, murine, non-human primate, avian, or shark.
  • the single domain antibody may be a shark variable new antigen receptor antibody fragment (VNAR).
  • VNAR shark variable new antigen receptor antibody fragment
  • the antibody may be derived from any type known to one of skill in the art including, but not limited to, IgA, IgD, IgE, IgG, IgM, IgY, IgW.
  • the antibody portion may be a glycoprotein.
  • the antibody portion may comprise one or more functional units, including but not limited to, 1, 2, 3, 4, and 5 units.
  • the antibody portion may comprise one or more units connected by one or more disulfide bonds.
  • the antibody portion may comprise one or more units connected by a peptide linker, for example, a scFv antibody.
  • the antibody may be a recombinant antibody including antibodies with amino acid mutations, substitutions, and/or deletions.
  • the antibody may be a recombinant antibody comprising chemical modifications.
  • an antibody portion of an antibody fusion is an amino acid sequence of palivizumab.
  • the palivizumab may have been modified to reduce binding to RSV.
  • an antibody portion of an antibody fusion is an amino acid sequence of BVK.
  • Non-limiting examples of antibody fragments include a variable domain, single domain antibody, constant domain, complementarity determining region (CDR), framework region, fragment antigen binding (Fab) region, antigen binding domain, fragment crystallizable (Fc) region, and combinations thereof, e.g., a single chain variable fragment (scFv).
  • an antigen binding domain is not limited to an antibody fragment capable of binding an antigen, but also includes antibody fragments derived from an antibody fragment capable of binding an antigen, wherein the derivatization comprises reducing or eliminating antigen binding.
  • an antigen binding domain is an antibody region comprising the CDR1, CDR2, and CDR3 of an antibody heavy chain, and the CDR1, CDR2, and CDR3 of an antibody light chain; wherein one or more of the CDRs has been mutated or otherwise altered in amino acid sequence identity to reduce or eliminate antigen binding.
  • an antigen binding domain is an antibody region comprising the CDR1, CDR2, and CDR3 of an antibody heavy chain, and the CDR1, CDR2, and CDR3 of an antibody light chain; wherein one or more of the CDRs has been mutated or otherwise altered in amino acid sequence identity to reduce or eliminate antigen binding, and one or more of the CDRs has been modified by insertion of a Kvl .3 inhibitor, where the modifications may occur at the same or different CDRs.
  • an antigen binding fragment comprises a CDR1, CDR2, and CDR3 of only a heavy chain sequence or only a light chain sequence, where one or more CDRs are modified by insertion of a Kvl .3 inhibitor and/or reduction or elimination of antigen binding.
  • an antigen binding fragment may be a single chain or dual chain connected, e.g., by disulfide bonds.
  • a composition (e.g., insert, antibody fusion protein) comprises "at least a portion" of an antibody or antibody fragment.
  • "at least a portion” indicates that at least about 80%, 85%, 90%, or 95% of the length of the antibody or antibody fragment is present in the composition.
  • an antibody fusion comprising at least a portion of heavy chain having SEQ ID NO: 2 (450 amino acids), comprises at least about 360 amino acids (80%), 382 amino acids (85%), 405 amino acids (90%) or 427 amino acids (95%) of the heavy chain.
  • the "at least a portion of may be a continuous amino acid sequence, or the sum of two continuous amino acid sequences that are separated by a Kvl .3 inhibitor.
  • an antibody fusion comprising a Kvl .3 inhibitor and at least a portion of an antibody variable domain may comprise a first continuous amino acid sequence of the antibody variable domain, the Kvl.3 inhibitor, and a second continuous amino acid sequence of the antibody variable domain, where the first and second continuous amino acid sequences of the antibody variable domain add up to at least about 80%, 85%, 90%, or 95% of the sequence length of an antibody variable domain.
  • an antibody fusion comprises at least a portion of an antibody or an antibody fragment selected from: an antibody variable domain and/or an antigen binding fragment (e.g., a fragment comprising a CDR1, CDR2, and CDR3 of an antibody heavy chain and/or antibody light chain); wherein the antibody fusion comprises a first antibody or antibody fragment region, a Kvl .3 inhibitor, and a second antibody or antibody fragment region; and wherein the "at least a portion" indicates that the sum of the length of the first antibody or antibody fragment region and the length of the second antibody or antibody fragment region is at least about 80%, 85%, 90%, or 95% of the length of the antibody variable domain and/or antigen binding fragment.
  • an antibody variable domain and/or an antigen binding fragment e.g., a fragment comprising a CDR1, CDR2, and CDR3 of an antibody heavy chain and/or antibody light chain
  • the antibody fusion comprises a first antibody or antibody fragment region, a Kvl .3 inhibitor, and a second antibody or antibody fragment region
  • a Kvl.3 inhibitor antibody fusion may comprise a Kvl.3 inhibitor selected from SEQ ID NOS: 13, 15, 131, and 36-63 positioned within a CDR of at least a portion of an antibody variable domain.
  • the CDR may be a CDR1, CDR2, or CDR3 of the heavy chain, or the CDR1, CDR2, or CDR3 of the light chain.
  • a Kvl.3 inhibitor antibody fusion may comprise a first chain comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOS: 7-11, 64-93, and 33-35.
  • a Kvl.3 inhibitor antibody fusion may comprise a first chain comprising a sequence of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids from any one of SEQ ID NOS: 7-11, 64-93, and 33-35.
  • nucleotide constructs comprising a nucleotide sequence encoding for a Kvl .3 inhibitor antibody fusion comprising a first chain comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOS: 7-11, 64-93 and 33-35.
  • the nucleotide construct may be a plasmid for expression in a host cell. For example, a mammalian or bacterial expression plasmid.
  • a Kvl.3 inhibitor antibody fusion may comprise a first chain comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOS: 7-11, 64-93, and 33-35; and a second chain comprising an ammo acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOS: 1-6, 93-100.
  • a Kvl .3 inhibitor antibody fusion may comprise a first chain comprising a sequence of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids from any one of SEQ ID NOs: 7-11, 64-93, and 33-35; and a second chain comprising an amino acid sequence of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids from any one of SEQ ID NOs: 1-6, 93-100.
  • the first chain may comprise a heavy chain variable domain of an antibody and the second chain may comprise a light chain of an antibody, and vice versa.
  • the first and second chains may be connected by one or more disulfide bonds.
  • the Kvl.3 inhibitor antibody fusions disclosed herein comprise one or more antibody portions.
  • An antibody portion of an antibody fusion is a sequence of amino acids from an antibody.
  • An antibody portion may comprise an entire antibody sequence or a fragment thereof.
  • An antibody portion may comprise an antibody heavy chain, antibody light chain, or a combination thereof.
  • An antibody portion may comprise two or more antibody chains or portions thereof.
  • An antibody portion may comprise three or more antibody chains or portions thereof.
  • An antibody portion may comprise four or more antibody chains or portions thereof.
  • an antibody portion comprises a variable domain comprising one or more CDRs.
  • the antibody portion comprises a variable domain that has been modified or otherwise engineered to reduce or eliminate antigen binding.
  • the antibody portion of Kvl .3 inhibitor antibody fusions described herein may comprise one or more mutations and/or modifications which reduce complement dependent and antibody -dependent cell-mediated cytotoxicities (ADCC).
  • ADCC complement dependent and antibody -dependent cell-mediated cytotoxicities
  • an antibody portion of a fusion has the following mutations: E233P, L234V, L235A, AG236, A327G, A330S, and P331S.
  • the antibody portion may comprise an entire antibody molecule or any polypeptide comprising fragment of an antibody including, but not limited to, heavy chain, light chain, variable domain, constant domain, complementarity determining region (CDR), antigen binding fragment, single domain antibody, framework region, fragment antigen binding (Fab) region, Fab', F(ab')2, F(ab')3, Fab', fragment crystallizable (Fc) region, single chain variable fragment (scFV), di-scFv, single domain antibody, trifunctional antibody, chemically linked F(ab')2, and any combination thereof.
  • an antibody heavy chain may comprise an entire heavy chain or a portion of a heavy chain.
  • variable domain or region thereof derived from a heavy chain may be referred to as a heavy chain or a region of a heavy chain.
  • an antibody light chain may comprise an entire light chain or a portion of a light chain.
  • a variable domain or region thereof derived from a light chain may be referred to as a light chain or a region of a light chain.
  • a single domain antibody includes, but is not limited to, a single monomeric variable antibody domain, for example, a shark variable new antigen receptor antibody fragment (VNAR).
  • VNAR shark variable new antigen receptor antibody fragment
  • the antibody may be derived from any type known to one of skill in the art including, but not limited to, IgA, IgD, IgE, IgG, IgM, IgY, IgW.
  • the antibody portion may comprise one or more units, including but not limited to, 1, 2, 3, 4, and 5 units.
  • Functional units may include, but are not limited to, non-antibody portions, heavy chain, light chain, variable domain, antigen binding fragment, single domain antibody, constant domain, complementarity determining region (CDR), framework region, fragment antigen binding (Fab) region, Fab', F(ab')2, F(ab')3, Fab', fragment crystallizable (Fc) region, single chain variable fragment (scFV), di-scFv, single domain antibody, trifunctional antibody, chemically linked F(ab')2, and any combination or fragments thereof.
  • Non-antibody portions include, but are not limited to, carbohydrates, lipids, small molecules and therapeutic peptides.
  • the antibody portion may comprise one or more units connected by one or more disulfide bonds.
  • the antibody portion may comprise one or more units connected by a peptide linker, for example, a scFv antibody.
  • the antibody may be a recombinant antibody including antibodies with amino acid mutations, substitutions, and/or deletions.
  • the antibody may be a recombinant antibody comprising chemical modifications.
  • the antibody may comprise a whole or part of an antibody-drug conjugate.
  • an antibody portion comprises one or more contiguous amino acid sequences.
  • an antibody portion comprises a first amino acid sequence, a Kvl .3 inhibitor, and a second amino acid sequence.
  • the total antibody portion may comprise at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or more amino acids.
  • the first amino acid sequence of the antibody portion may comprise from about 10 to about 100 amino acids, from about 10 to about 75 amino acids, from about 10 to about 50 amino acids, or from about 10 to about 30 amino acids.
  • the second amino acid sequence may comprise from about 10 to about 400 amino acids, from about 10 to about 300 amino acids, from about 10 to about 200 amino acids, from about 10 to about 100 amino acids, or from about 10 to about 100 amino acids.
  • the first amino acid sequence of the antibody portion comprises at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150 or more amino acids.
  • the second amino acid sequence of the antibody portion comprises at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 175, 200, 250, 300 or more amino acids.
  • An antibody portion of a Kvl .3 inhibitor antibody fusion may comprise a first chain comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOS: 1-6, 93-100.
  • the antibody portion of the Kvl.3 inhibitor antibody fusion may comprise a second chain comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOS: 1-6, 93-100.
  • An antibody portion of a Kvl.3 inhibitor antibody fusion may comprise a first chain comprising a sequence of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids from any one of SEQ ID NOs: 1-6, 93-100.
  • the antibody portion of the Kvl.3 inhibitor antibody fusion may comprise a second chain comprising an amino acid sequence of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acids from any one of SEQ ID NOs: 1-6, 93-100.
  • An antibody portion of a Kvl.3 inhibitor antibody fusion may comprise a palivizumab CDR or other region thereof.
  • An antibody portion of a Kvl.3 inhibitor antibody fusion may comprise a heavy chain and a light chain. The heavy and light chain may be connected by a linker or by a disulfide bond.
  • the antibody portion of the Kvl .3 inhibitor antibody fusion may comprise at least a portion of a variable domain.
  • the antibody portion may comprise 1, 2, 3, 4, 5 or more variable domains or portions thereof.
  • the antibody portion of the Kvl .3 inhibitor antibody fusion may comprise at least a portion of a constant domain.
  • the antibody portion may comprise 1, 2, 3, 4, 5 or more constant domains or portions thereof.
  • the antibody portion of the Kvl .3 inhibitor antibody fusion may comprise at least a portion of a complementarity-determining region (CDR).
  • CDR complementarity-determining region
  • the antibody portion may comprise 1, 2, 3, 4, 5 or more CDRs or portions thereof.
  • An antibody portion of a Kvl .3 inhibitor antibody fusion may comprise a first CDR comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOS: 21-32.
  • An antibody portion of a Kvl.3 inhibitor antibody fusion may comprise a second CDR comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOS: 21-32.
  • An antibody portion of a Kvl .3 inhibitor antibody fusion may comprise a third CDR comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to any one of SEQ ID NOS: 21-32, 101-123.
  • the first CDR, second CDR, and/or third CDR is modified by an addition, deletion and/or amino acid mutation.
  • the first CDR, second CDR and/or third CDR is modified by insertion of a Kvl.3 peptide inhibitor, extension peptide, linker, or combination thereof.
  • a first CDR comprising an amino acid sequence identical to a sequence selected from SEQ ID NOS: 26 and 117-123 is modified to comprise an insertion sequence comprising a Kvl.3 peptide inhibitor, an extension peptide, a linker, or a combination thereof.
  • a first CDR comprising an amino acid sequence identical to SEQ ID NO: 29 is modified to comprise an insertion sequence comprising a Kvl .3 peptide inhibitor, an extension peptide, a linker, or a combination thereof.
  • the antibody portion of a Kvl.3 inhibitor antibody fusion comprises one or more antibody portions selected from SEQ ID NOS: 125-128.
  • the antibody portion of a Kvl.3 inhibitor antibody fusion comprises at least a portion of a variable domain comprising SEQ ID NO: 129 and/or SEQ ID NO: 130. In some cases, the antibody fusion comprises at least about 80%, 85%, 90%, or 95% of the variable domain.
  • the antibody portion of a Kvl.3 inhibitor antibody is not specific for a mammalian target.
  • the antibody is an anti-viral antibody.
  • the antibody is an anti-bacterial antibody.
  • the antibody is an anti-parasitic antibody.
  • the antibody is an anti-fungal antibody.
  • the antibody portion is derived from an antibody vaccine.
  • a Kvl.3 inhibitor antibody comprises an antibody sequence from, but not limited to, actoxumab, bezlotoxumab, CR6261, edobacomab, efungumab, exbivirumab, felvizumab, foravirumab, ibalizumab (TMB-355, TNX-355), libivirumab, motavizumab, nebacumab, pagibaximab, palivizumab, panobacumab, rafivirumab, raxibacumab, regavirumab, sevirumab (MSL-109), suvizumab, tefibazumab, tuvirumab, and urtoxazumab.
  • a Kvl.3 inhibitor antibody comprises an antibody sequence from antibodies targeting Clostridium difficile, Orthomyxoviruses (Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus, Thogotovirus), Escherichia coli, Candida, Rabies, Human Immunodeficiency Virus, Hepatitis, Staphylococcus, Respiratory Syncytial Virus, Pseudomonas aeruginosa, Bacillus anthracis, Cytomegalovirus, or Staphylococcus aureus.
  • Orthomyxoviruses Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus, Thogotovirus
  • Escherichia coli Candida
  • Rabies Human Immunodeficiency Virus
  • Hepatitis Hepatitis
  • Staphylococcus Respiratory Syncytial Virus
  • Pseudomonas aeruginosa Bacillus anthracis
  • a Kvl.3 inhibitor antibody may comprise an antibody sequence from an anti-viral antibody.
  • the anti-viral antibody may be directed against an epitope of a viral protein.
  • the anti-bacterial antibody may target one or more viruses including, but not limited to, Adenoviruses, Herpesviruses, Poxviruses,
  • the viral protein may be from a respiratory syncytial virus.
  • the viral protein may be an F protein of the respiratory syncytiral virus.
  • the epitope may be in the A antigenic site of the F protein.
  • the anti -viral antibody may be based on or derived from palivizumab.
  • the antibody may be based on or derived from an anti -viral vaccine.
  • the anti -viral antibody may be based on or derived from exbivirumab, foravirumab, libiviramab, rafivirumab, regavirumab, sevirumab, tuvirumab, felvizumab, motavizumab, palivizumab, and/or suvizumab.
  • a Kvl.3 inhibitor antibody may comprise an antibody sequence from an anti-viral antibody G.
  • the antibody portion may comprise at least a portion of an anti -viral antibody G.
  • the antibody portion may comprise an amino acid sequence that is at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more identical to at least a portion of an anti-viral antibody G.
  • the antibody portion comprises an amino acid sequence of an anti-viral antibody M.
  • an antibody portion of a Kvl .3 inhibitor antibody fusion comprises a palivizumab antibody sequence.
  • the antibody portion may comprise an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more identical to at least a portion of a palivizumab antibody.
  • the antibody portion comprises an amino acid sequence at least 80%, 85%, 90%, or 95% identical to a sequence selected from one or more of: 1-3, 21-26, 93-124.
  • the antibody portion comprises at least 10 contiguous amino acids of a sequence selected from one or more of: 1-3, 21-26, 93-124.
  • a Kvl.3 inhibitor antibody may comprise an antibody sequence from an exbivirumab, foravirumab, libivirumab, rafivirumab, regavirumab, sevirumab, tuvirumab, felvizumab, motavizumab, palivizumab, and/or suvizumab antibody.
  • the antibody portion may comprise at least a portion of an exbivirumab, foravirumab, libivirumab, rafivirumab, regavirumab, sevirumab, tuvirumab, felvizumab, motavizumab, palivizumab, and/or suvizumab antibody.
  • An antibody Kvl.3 inhibitor antibody may comprise an antibody sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more identical to at least a portion of an exbivirumab, foravirumab, libivirumab, rafivirumab, regavirumab, sevirumab, tuvirumab, felvizumab, motavizumab, palivizumab, and/or suvizumab antibody.
  • a Kvl.3 inhibitor antibody may comprise an antibody sequence from an anti-bacterial antibody.
  • the anti-bacterial antibody may be directed against an epitope of a bacterial protein.
  • the anti-bacterial antibody may target bacteria including, but not limited to, Acetobacter aurantius, Agrobocterium radiobacter, Anaplasma phagocy tophi lum, Azorhizobium caulinodans, Bacillus anthracis, Bacillus brevis, Bacillus cereus, Bacillus subtilis, Bacteroides fragilis, Bacteroides gingivalis, Bacteroides melaninogenicus, Bartonella quintana, Bordetella bronchiseptica, Bordetella pertussis, Borrelia burgdorferi, Brucella abortus, Brucella melitensis, Brucella suis, Burkholderia mallei, Burkholderia pseudomallei, Burkholderia cepacia,
  • Peptostreptococcus Porphyromonas gingivalis, Prevotella melaninogenica, Pseudomonas aeruginosa, Rhizobium radiobacter, Rickettsia rickettsii, Rothia dentocariosa, Salmonella enteritidis, Salmonella typhi, Salmonella typhimurium, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Stenotrophomonas maltophilia, Streptococcus pneumoniae, Streptococcus pyogenes, Treponema pallidum, Treponema denticola, Vibrio cholerae, Vibrio comma, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica and Yersinia pseudotuberculosis .
  • the antibody may be based on or derived from a bacterial vaccine.
  • the anti -viral antibody may be based on or derived from nebacumab, panobacumab, raxibacumab, edobacomab, pagibaximab, and/or tefibazumab.
  • a Kvl.3 inhibitor antibody may comprise an antibody sequence from an anti-bacterial antibody G.
  • the antibody portion may comprise at least a portion of an anti-bacterial antibody G.
  • the antibody portion may comprise an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more identical to at least a portion of an anti-bacterial antibody G.
  • the antibody portion comprises an amino acid sequence based on or derived from an antibacterial antibody M.
  • the antibody portion may comprise an antibody sequence from a Nebacumab, Panobacumab, Raxibacumab, Edobacomab, Pagibaximab, and/or Tefibazumab antibody.
  • the antibody portion may comprise an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more identical to at least a portion of a nebacumab, panobacumab, raxibacumab, edobacomab, pagibaximab, and/or tefibazumab antibody.
  • the antibody portion may comprise an antibody sequence from an anti-parasitic antibody.
  • the antiparasitic antibody may be directed against an epitope of a parasite protein.
  • the anti-parasitic antibody may target parasites or parasite proteins including, but not limited to parasites Acanthamoeba, Balamuthia mandrillaris, Babesia (B. divergens, B. bigemina, B. equi, B. microfti, B.
  • Ascaris lumbricoides Baylisascaris procyonis, Brugia malayi, Brugia timori, Dioctophyme renale, Dracunculus medinensis, Enterobius vermicularis, Enterobius gregorii, Halicephalobus gingivalis, Loa filaria, Mansonella streptocerca, Onchocerca volvulus, Strongyloides stercoralis, Thelazia californiensis, Thelazia callipaeda, Toxocara canis, Toxocara cati, Trichinella spiralis, Trichinella britovi, Trichinella nelsoni, Trichinella nativa, Trichuris trichiura, Trichuris vulpis, Wuchereria bancrofti, Archiacanthocephala, Moniliformis moniliformis,
  • the antibody portion may comprise an antibody sequence from an anti-parasitic antibody G.
  • the antibody portion may comprise at least a portion of an anti -parasitic antibody G.
  • the antibody portion may comprise an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more identical to at least a portion of an anti -parasitic antibody G.
  • the antibody portion may comprise an antibody sequence from an anti-fungal antibody.
  • the antibacterial antibody may be directed against an epitope of a fungal protein.
  • the anti-fungal antibody may target fungi or fungal proteins including, but not limited to Cryptococcus neoformans, Cryptococcus gattii, Candida albicans, Candida tropicalis, Candida stellatoidea, Candida glabrata, Candida krusei, Candida parapsilosis, Candida guilliermondii, Candida viswanathii, Candida lusitaniae, Rhodotorula mucilaginosa,
  • the anti-fungal antibody may be based on or derived from efungumab.
  • the antibody portion may comprise an antibody sequence from an anti-fungal antibody G.
  • the antibody portion may comprise at least a portion of an anti -fungal antibody G.
  • the antibody portion may comprise an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more identical to at least a portion of an anti -fungal antibody G.
  • the antibody portion may comprise an antibody sequence from a trastuzumab antibody G antibody.
  • the antibody portion may comprise at least a portion of a trastuzumab antibody G antibody.
  • the antibody portion may comprise an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more identical to at least a portion of a trastuzumab antibody G antibody.
  • the antibody portion may comprise an antibody sequence from an anti-Her2 antibody.
  • the antibody portion may comprise at least a portion of an anti-Her2 antibody.
  • the antibody portion may comprise an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or 97% or more identical to at least a portion of an anti-Her2 antibody.
  • the antibody portion may comprise an antibody sequence from an anti-cancer antibody.
  • anti -cancer antibody include, but are not limited to, abciximab, adalimumab, alemtuzumab, basiliximab, belimumab, bevacizumab, brentuximab, canakinumab, certolizumab, cetuximab, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab, infliximab, ipilimumab, muromonab-cd3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab, trastuzumab.
  • the antibody portion of a Kvl .3 inhibitor antibody may comprise at least a portion of a human antibody.
  • the antibody portion may comprise at least a portion of a humanized antibody.
  • the antibody portion may comprise at least a portion of a chimeric antibody.
  • the antibody portion may be based on or derived from a human antibody.
  • the antibody portion may be based on or derived from a humanized antibody.
  • the antibody portion may be based on or derived from a chimeric antibody.
  • the antibody portion may be based on or derived from a monoclonal antibody.
  • the antibody portion may be based on or derived from a polyclonal antibody.
  • the antibody portion may comprise at least a portion of an antibody from a mammal, avian, reptile, amphibian, or a combination thereof.
  • the mammal may be a human.
  • the mammal may be a non-human primate.
  • the mammal may be a dog, cat, sheep, goat, cow, rabbit, or mouse.
  • Kvl.3 inhibitor comprising an amino acid sequence selected from SEQ ID NOS: 12-15, 131, and 36-63, and compositions comprising the Kvl.3 inhibitor.
  • the Kvl .3 inhibitor comprises SEQ ID NO: 36
  • XI is S or K
  • X2 is S or P
  • X3 is P or K
  • X4 is P or L
  • X5 is K or P
  • X6 is R or G
  • X7 is T or indicates no amino acid present at this position
  • X8 is K or P
  • X9 is N or Y
  • X10 is Y or N
  • XI 1 is Y, R, F or G
  • Zl is C, A, G, S, I, or L
  • Z2 is C, A, G, S, I, or L
  • Z3 is C, A, G, S, I, or L
  • Z4 is C, A, G, S, I, or L
  • Z5 is C, A, G, S, I, or
  • the Kvl .3 peptide inhibitor comprises SEQ ID NO: 37, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 37 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 38, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 38 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 39, or an amino acid sequence diffenng in amino acid sequence from SEQ ID NO: 39 by fewer than 4 amino acid deletions and/or substitutions.
  • the Kvl .3 peptide inhibitor comprises SEQ ID NO: 40, or an amino acid sequence diffenng in amino acid sequence from SEQ ID NO: 40 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 41, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 41 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 42, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 42 by fewer than 4 amino acid deletions and/or substitutions.
  • the Kvl .3 peptide inhibitor comprises SEQ ID NO: 43, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 43 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 44, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 44 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 45, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 45 by fewer than 4 amino acid deletions and/or substitutions.
  • the Kvl .3 peptide inhibitor comprises SEQ ID NO: 46, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 46 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 47, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 47 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 48, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 48 by fewer than 4 amino acid deletions and/or substitutions.
  • the Kvl .3 peptide inhibitor comprises SEQ ID NO: 49, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 49 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 50, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 50 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 51, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 51 by fewer than 4 amino acid deletions and/or substitutions.
  • the Kvl .3 peptide inhibitor comprises SEQ ID NO: 52, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 52 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 53, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 53 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 54, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 54 by fewer than 4 amino acid deletions and/or substitutions.
  • the Kvl .3 peptide inhibitor comprises SEQ ID NO: 55, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 55 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 56, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 56 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 57, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 57 by fewer than 4 amino acid deletions and/or substitutions.
  • the Kvl .3 peptide inhibitor comprises SEQ ID NO: 58, or an amino acid sequence diffenng in amino acid sequence from SEQ ID NO: 58 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 59, or an amino acid sequence diffenng in amino acid sequence from SEQ ID NO: 59 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 60, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 60 by fewer than 4 amino acid deletions and/or substitutions.
  • the Kvl .3 peptide inhibitor comprises SEQ ID NO: 61, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 61 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 62, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 62 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 63, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 63 by fewer than 4 amino acid deletions and/or substitutions. In some embodiments, the Kvl .3 peptide inhibitor comprises SEQ ID NO: 131, or an amino acid sequence differing in amino acid sequence from SEQ ID NO: 131 by fewer than 4 amino acid deletions and/or substitutions.
  • Kvl.3 peptide inhibitors include Toxin A, Toxin B, Toxin XX, Toxins C-Z, Toxins AA-CC, and Shk-toxin (SEQ ID NO: 131,
  • the therapeutic peptide may be connected to/within a CDR of an antibody variable domain, optionally with one or more extension peptides and/or linkers. In some cases, the variable domain has been modified to reduce antigen binding.
  • a Kvl.3 inhibitor peptide provided herein binds to a cation channel, such as a potassium, sodium, and/or calcium channel; and or an anion channel such as a chlorine channel.
  • Therapeutic peptides may bind to both receptors and voltage-gated channels.
  • Non-limiting examples of channels or receptors include kanate; a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMP A); N-methyl-D- aspartate (NMD A) and acetylcholine receptors (such as .alpha.9/.alpha.10 subtype (nAChR)); serotonin (5- hydroxytryptamine, 5-HT) receptors; and glycine and .gamma. -butyric (GAB A) receptors.
  • Intracellular receptors include cyclic AMP (cAMP), cyclic GMP (cGMP), Ca2+, and G-protein receptors.
  • a therapeutic peptide binds to a voltage gated channel, such as Kvl .3, but may also bind to one or more of the following channels: Kvl. l, Kvl.2, Kvl.4, Kvl .5, Kvl .6, Kvl .7, Kv2.1 , Kv3.1 , Kv3.2, Kvl l .1 (hERG), Kcl . l, Kc2.1, Kc3.1, KCa3.1, Navl .2, Navl.4, Navl.5, and Cavl .2 channels.
  • a therapeutic peptide may be a naturally occurring toxin, or modified from a naturally occurring toxin, the naturally occurring toxin being from a snake, scorpion, spider, bee, snail or sea anemone.
  • a therapeutic peptide may be a synthetic peptide. In some cases, a therapeutic peptide comprises from about 1 to about 5, or 1, 2, 3, 4 or 5 disulfide bonds.
  • a therapeutic peptide is an inhibiting peptide which includes any toxin-based therapeutic that decreases or eliminates a biological activity that normally results based on the interaction of a compound with a receptor and/or channel, including biosynthetic activity, catalytic activity, receptor activity, signal transduction pathway activity, gene transcription or translation, cellular protein transport, and the like.
  • the inhibiting peptide is an inhibitor of Kvl .3.
  • the inhibiting peptide is an inhibitor of Kvl .l, Kvl.2, Kvl.3, Kvl.4, Kvl.5, Kvl .6, Kvl .7, Kv2.1 , Kv3.1, Kv3.2, Kvl l .1, Kcl. l, Kc2.1, Kc3.1, Navl .2, Navl .4, KCa3.1, Navl .5, and Cavl .2, or any combination thereof.
  • a peptide inhibitor of Kvl .3 also inhibits one or more of Kvl .
  • Kvl.3 inhibitor is inclusive of a molecule that binds to a receptor and/or voltage-gated channel, such as Kvl.
  • a Kvl.3 inhibitor comprising SEQ ID NO: 13 binds to Kvl.3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kvl .1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kvl.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kvl .4. In some embodiments, a Kvl.3 inhibitor comprising SEQ ID NO: 13 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kvl 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kc l . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 13 binds to Navl .5. In some embodiments, a Kvl 3 inhibitor comprising SEQ ID NO: 13 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 15 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 15 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to K l .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Kv3.2. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 15 binds to Kv 1 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 15 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kvl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kvl 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 36 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kvl 1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to K l .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kv3.2. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 37 binds to Kv 1 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 37 binds to Cavl .2. In some cases, the Kvl .3 mhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 38 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 38 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 38 binds to Kv 1.4. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 38 binds to Kvl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Kvl .6.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 38 binds to Kv3.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 38 binds to Kv3.2. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 38 binds to Kv 1 1.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Kcl . l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Navl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 38 binds to Cavl .2.
  • the Kvl .3 inhibitor is present in a composition and/or antibody fusion.
  • a Kvl .3 inhibitor that "binds to" a channel inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kvl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kv3.2. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 39 binds to Kv 1 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 39 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 40 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 40 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kvl 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 40 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 41 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 41 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 41 binds to Kv 1.4. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 41 binds to Kvl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Kvl .6.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 41 binds to Kv3.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 41 binds to Kv3 2. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 41 binds to Kv 1 1.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Kcl . l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Navl .4. In some embodiments, a K l .3 inhibitor comprising SEQ ID NO: 41 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Navl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 41 binds to Cavl .2.
  • the Kvl .3 inhibitor is present in a composition and/or antibody fusion.
  • a Kvl .3 inhibitor that "binds to" a channel inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 42 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 42 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 42 binds to Kv 1.4. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 42 binds to Kvl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Kvl .6.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Kv3.2. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 42 binds to Kv 1 1.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Kcl . l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Navl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 42 binds to Cavl .2.
  • the Kvl .3 inhibitor is present in a composition and/or antibody fusion.
  • a Kvl .3 inhibitor that "binds to" a channel inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 43 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 43 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kvl 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Navl 2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 43 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kvl .1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 44 binds to Kv 1.4. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 44 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kv3.2. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 44 binds to Kv 1 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 44 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 45 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 45 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kvl 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 45 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 46 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 46 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kvl 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 46 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 47 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 47 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kvl 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 47 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 48 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 48 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to K l .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kvl l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kcl . l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kc2.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Kc3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Navl .2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Navl .4.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 48 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 49 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 49 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kv3.2. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 49 binds to Kv 1 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 49 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kvl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kv3.2. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 50 binds to Kv 1 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 50 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 51 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 51 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 51 binds to Kv 1.4. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 51 binds to Kvl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Kvl .6.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 51 binds to Kv3.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 51 binds to Kv3.2. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 51 binds to Kv 1 1.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Kcl . l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Navl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 51 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel. [0091] In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 52 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 52 binds to Kvl .2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kv 1.4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kvl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kv3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kvl l . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Kc3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 52 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kvl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kvl l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kcl . l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kc2.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Kc3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Navl .2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Navl .4.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 53 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kvl .1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kvl l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kcl . l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kc2.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Kc3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Navl .2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Navl .4.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 54 binds to Navl .5. In some embodiments, a Kvl 3 inhibitor comprising SEQ ID NO: 54 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kvl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kvl l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kcl . l .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kc2.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Kc3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Navl .2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Navl .4.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 55 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kvl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kvl 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 56 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kvl 1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to K l . .
  • a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kv3.2.
  • a Kv 1.3 inhibitor comprising SEQ ID NO : 57 binds to Kv 1 1.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Navl .2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 57 binds to Cavl .2. In some cases, the Kvl .3 mhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 58 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 58 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 58 binds to Kv 1.4. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 58 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Kv3.2.
  • a Kv 1.3 inhibitor comprising SEQ ID NO : 58 binds to Kv 1 1.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Navl .2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 8 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 58 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kvl .3. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kvl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kv3.2.
  • a Kv 1.3 inhibitor comprising SEQ ID NO : 59 binds to Kv 1 1.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Navl .2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 59 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 60 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 60 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kvl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kv3.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kvl 1.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Navl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to KCa3.1.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 60 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 61 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 61 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 61 binds to Kv 1.4. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 61 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 61 binds to Kv3.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 61 binds to Kv3 2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Kvl 1.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Navl .2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 61 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 62 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 62 binds to Kvl .2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO : 62 binds to Kv 1.4. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 62 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Kvl .6. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Kvl .7. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Kv3.2.
  • a Kv 1.3 inhibitor comprising SEQ ID NO : 62 binds to Kv 1 1.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Kcl . l . In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Kc3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Navl .2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Navl .4. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Navl .5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 62 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl .3 inhibitor that "binds to" a channel, inhibits the channel.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Kvl .3. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO : 63 binds to Kv 1.1. In some embodiments, a Kv 1.3 inhibitor comprising SEQ ID NO: 63 binds to Kvl.2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Kv 1.4. In some embodiments, a Kvl.3 inhibitor comprising SEQ ID NO: 63 binds to Kvl .5.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Kvl .6. In some embodiments, a K l .3 inhibitor comprising SEQ ID NO: 63 binds to Kvl .7. In some embodiments, a Kvl.3 inhibitor comprising SEQ ID NO: 63 binds to Kv2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Kv3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Kv3.2.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Kvl 1.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Kcl .l . In some embodiments, a Kvl.3 inhibitor comprising SEQ ID NO: 63 binds to Kc2.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Kc3.1. In some embodiments, a Kvl.3 inhibitor comprising SEQ ID NO: 63 binds to Navl2. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Navl .4.
  • a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to KCa3.1. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Navl.5. In some embodiments, a Kvl .3 inhibitor comprising SEQ ID NO: 63 binds to Cavl .2. In some cases, the Kvl .3 inhibitor is present in a composition and/or antibody fusion. In some cases, a Kvl.3 inhibitor that "binds to" a channel, inhibits the channel.
  • An antibody fusion may comprise a therapeutic peptide inhibitor comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to SEQ ID NO: 13.
  • An antibody fusion may comprise a therapeutic peptide inhibitor comprising a sequence of about 5, 10, 20, or all amino acids from SEQ ID NO: 13.
  • An antibody fusion may comprise a therapeutic peptide inhibitor comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to SEQ ID NO: 15.
  • An antibody fusion may comprise a therapeutic peptide inhibitor comprising a sequence of about 5, 10, 20, or all amino acids from SEQ ID NO: 15.
  • An antibody fusion may comprise a variant of a therapeutic peptide inhibitor, which includes a peptide having one or more amino acid additions, deletions, or substitutions as compared to a therapeutic peptide inhibitor selected from any one of SEQ ID NOS: 13 and 15.
  • Variants of therapeutic peptide inhibitors include those having one or more conservative amino acid substitutions.
  • a conservative substitution may involve a substitution found in one of the following conservative substitutions groups: Group 1: Alanine (Ala; A), Glycine (Gly; G), Serine (Ser; S), Threonine (Thr; T); Group 2: Aspartic acid (Asp; D), Glutamic acid (Glu; E); Group 3: Asparagine (Asn; N), Glutamine (Gin; Q); Group 4: Arginine (Arg; R), Lysine (Lys; K), Histidine (His; H); Group 5: Isoleucine (He; I), Leucine (Leu; L), Methionine (Met; M), Valine (Val; V); and Group 6: Phenylalanine (Phe; F), Tyrosine (Tyr; Y), Tryptophan (Trp; W).
  • amino acids may be grouped into conservative substitution groups by similar function, chemical structure, or composition.
  • an aliphatic grouping may include, for purposes of substitution, Gly, Ala, Val, Leu, and He.
  • Other groups including amino acids that are considered conservative substitutions for one another may include: sulfur-containing: Met and Cys; acidic: Asp, Glu, and Asn; small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro, and Gly; polar, negatively charged residues and their amides: Asp, Asn, and Glu; polar, positively charged residues: His, Arg, and Lys; large aliphatic, nonpolar residues: Met, Leu, He, Val, and Cys; and large aromatic residues: Phe, Tyr, and Trp.
  • a Kvl .3 inhibitor antibody fusion may comprise a Kvl.3 peptide inhibitor comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to SEQ ID NO: 13.
  • a Kvl .3 inhibitor antibody fusion may comprise Kvl .3 peptide inhibitor comprising a sequence of about 5, 10, 20, or all amino acids from SEQ ID NO: 13.
  • a Kvl .3 inhibitor antibody fusion may comprise a Kvl .3 peptide inhibitor comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to SEQ ID NO: 15.
  • a Kvl .3 inhibitor antibody fusion may comprise Kvl .3 peptide inhibitor comprising a sequence of about 5, 10, 20, or all amino acids from SEQ ID NO: 15.
  • An antibody fusion may comprise a therapeutic peptide inhibitor comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to a sequence selected from SEQ ID NOS: 36-63, 131.
  • An antibody fusion may comprise a therapeutic peptide inhibitor comprising a sequence of about 5, 10, 20, or all amino acids from a sequence selected from SEQ ID NOS: 36-63, 131.
  • An antibody fusion may comprise a variant of a therapeutic peptide inhibitor, which includes a peptide having one or more amino acid additions, deletions, or substitutions as compared to a therapeutic peptide inhibitor selected from any one of SEQ ID NOS: 36-63, 131.
  • Variants of therapeutic peptide inhibitors include those having one or more conservative amino acid substitutions.
  • a conservative substitution may involve a substitution found in one of the following conservative substitutions groups: Group 1 : Alanine (Ala; A), Glycine (Gly; G), Serine (Ser; S), Threonine (Thr; T); Group 2: Aspartic acid (Asp; D), Glutamic acid (Glu; E); Group 3 : Asparagine (Asn; N), Glutamine (Gin; Q); Group 4: Arginine (Arg; R), Lysine (Lys; K), Histidine (His; H); Group 5 : Isoleucine (lie; I), Leucine (Leu; L), Methionine (Met; M), Valine (Val; V); and Group 6: Phenylalanine (Phe; F), Tyrosine (Tyr; Y), Tryptophan (Trp; W).
  • amino acids may be grouped into conservative substitution groups by similar function, chemical structure, or composition.
  • an aliphatic grouping may include, for purposes of substitution, Gly, Ala, Val, Leu, and He.
  • Other groups including amino acids that are considered conservative substitutions for one another may include: sulfur-containing: Met and Cys; acidic: Asp, Glu, and Asn; small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro, and Gly; polar, negatively charged residues and their amides: Asp, Asn, and Glu; polar, positively charged residues: His, Arg, and Lys; large aliphatic, nonpolar residues: Met, Leu, He, Val, and Cys; and large aromatic residues: Phe, Tyr, and Trp.
  • Kvl .3 inhibitor antibody fusion proteins may comprise one or more extension peptides and/or linkers.
  • a Kvl .3 peptide inhibitor is fused with one or more extension peptides within an insert portion into a CDPv or an antibody variable domain.
  • the insert portion replaces one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of the CDR.
  • the insert portion does not replace an amino acid of the CDR.
  • the insert portion may comprise: a first extension sequence, Kvl .3 peptide inhibitor, and a second extension sequence.
  • the first and second extension sequences may comprise amino acid sequences which form a coiled coil.
  • the first and second extension sequences may comprise amino acid sequences which form a beta sheet.
  • the insert portion may further comprise one or more linkers.
  • a linker comprises between 1 and 50 amino acids, between 1 and 20 amino acids, between 1 and 10 amino acids, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids.
  • a linker comprises at least 5, 6, 7, 8, 9, 10, 15, 20, or 30 amino acids.
  • the linker does not comprise regular secondary structure (e.g., beta strand, turn, helix).
  • the Kvl .3 antibody fusion may have Formula I.
  • the CDR fused with the Kvl .3 peptide inhibitor may be a CDR3 of an antibody light chain.
  • the CDR fused with the Kvl .3 peptide inhibitor may be a CDR2 of an antibody light chain.
  • the CDR fused with the Kvl .3 peptide inhibitor may be a CDR1 of an antibody light chain.
  • the CDR fused with the Kvl .3 peptide inhibitor may be a CDR3 of an antibody heavy chain.
  • the CDR fused with the Kvl .3 peptide inhibitor may be a CDR2 of an antibody heavy chain.
  • the CDR fused with the Kvl .3 peptide inhibitor may be a CDR1 of an antibody heavy chain.
  • a Kvl .3 inhibitor antibody fusion may comprise a first extension peptide comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to SEQ ID NO: 16.
  • a Kvl .3 inhibitor antibody fusion may comprise a second extension peptide comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to SEQ ID NO: 17.
  • a Kvl .3 inhibitor antibody fusion may comprise a first extension peptide comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to SEQ ID NO: 18.
  • a Kvl .3 inhibitor antibody fusion may comprise a second extension peptide comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to SEQ ID NO: 19.
  • a Kvl .3 inhibitor antibody fusion may comprise a linker comprising an amino acid sequence that is identical to or at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 97% identical to SEQ ID NO: 20.
  • Antibody fusion proteins may be expressed and purified by known recombinant and protein purification methods.
  • the activity of the antibody fusion protein is affected by expression and/or purification methods.
  • the activity of an antibody fusion protein configured for use as a therapeutic is enhanced or attenuated based on the identity of the expression vector, identity of the recombinant host, identity of the cell line, expression reaction conditions, purification methods, protein processing, or any combination thereof.
  • Expression reaction conditions include, but are not limited to, temperature, % C0 2 , media, expression time, cofactors, and chaperones.
  • Purification methods include, but are not limited to, purification temperatures, chromatography resins, protease inhibitors, and buffer compositions.
  • Antibody fusion proteins may be expressed by recombinant methods. Generally, a nucleic acid encoding an antibody fusion protein may be isolated and inserted into a replicable vector for further cloning (amplification of the DNA) or for expression. DNA encoding the antibody fusion protein may be prepared by PCR amplification and sequenced using conventional procedures (e.g., by using
  • nucleic acid encoding an antibody fusion protein is PCR amplified, restriction enzyme digested and gel purified.
  • the digested nucleic acid may be inserted into a replicable vector.
  • the replicable vector containing the digested antibody fusion protein insertion may be transformed or transduced into a host cell for further cloning (amplification of the DNA) or for expression.
  • Host cells may be prokaryotic or eukaryotic cells.
  • Polynucleotide sequences encoding polypeptide components (e.g. , antibody portion, Kvl .3 peptide inhibitor) of the antibody fusion proteins may be obtained by PCR amplification. Polynucleotide sequences may be isolated and sequenced from cells containing nucleic acids encoding the polypeptide components. Alternatively, or additionally, polynucleotides may be synthesized using nucleotide synthesizer or PCR techniques. Once obtained, sequences encoding the polypeptide components may be inserted into a recombinant vector capable of replicating and expressing heterologous polynucleotides in prokaryotic and/or eukaryotic hosts.
  • polypeptide components e.g. , antibody portion, Kvl .3 peptide inhibitor
  • phage vectors containing replicon and control sequences that are compatible with the host microorganism may be used as transforming vectors in connection with these hosts.
  • bacteriophage such as ⁇ TM-1 1 may be utilized in making a recombinant vector which may be used to transform susceptible host cells such as E. coli LE392.
  • Antibody fusion proteins may be expressed intracellularly (e.g., cytoplasm) or extracellularly (e.g., secretion).
  • the vector may comprise a secretion signal which enables translocation of the antibody fusion proteins to the outside of the cell.
  • Suitable host cells for cloning or expression of antibody fusion proteins-encoding vectors include prokaryotic or eukaryotic cells.
  • the host cell may be a eukaryotic.
  • eukaryotic cells include, but are not limited to, Human Embryonic Kidney (HEK) cell, Chinese Hamster Ovary (CHO) cell, fungi, yeasts, invertebrate cells (e.g., plant cells and insect cells), lymphoid cell (e.g. , YO, NSO, Sp20 cell).
  • suitable mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); baby hamster kidney cells (BHK); mouse Sertoli cells; monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TR1 cells; MRC 5 cells; and FS4 cells.
  • the host cell may be a prokaryotic cell (e.g., E. coli ).
  • Host cells may be transformed with vectors containing nucleotides encoding an antibody fusion proteins.
  • Transformed host cells may be cultured in media.
  • the media may be supplemented with one or more agents for inducing promoters, selecting transformants, or amplifying or expressing the genes encoding the desired sequences.
  • Methods for transforming host cells are known in the art and may include electroporation, calcium chloride, or polyethylene glycol/DMSO.
  • host cells may be transfected or transduced with vectors containing nucleotides encoding an antibody fusion proteins.
  • Transfected or transduced host cells may be cultured in media.
  • the media may be supplemented with one or more agents for inducing promoters, selecting transfected or transduced cells, or expressing genes encoding the desired sequences.
  • the expressed antibody fusion proteins may be secreted into and recovered from the periplasm of the host cells or transported into the culture media. Protein recovery from the periplasm may involve disrupting the host cell. Disruption of the host cell may comprise osmotic shock, sonication or lysis. Centrifugation or filtration may be used to remove cell debris or whole cells.
  • the antibody fusion proteins may be further purified, for example, by affinity resin chromatography.
  • antibody fusion proteins that are secreted into the culture media may be isolated therein.
  • Cells may be removed from the culture and the culture supernatant being filtered and concentrated for further purification of the proteins produced.
  • the expressed polypeptides may be further isolated and identified using commonly known methods such as polyacrylamide gel electrophoresis (PAGE) and Western blot assay.
  • PAGE polyacrylamide gel electrophoresis
  • Antibody fusion proteins production may be conducted in large quantity by a fermentation process.
  • Various large-scale fed-batch fermentation procedures are available for production of recombinant proteins.
  • Large-scale fermentations have at least 1000 liters of capacity, preferably about 1,000 to 100,000 liters of capacity. These fermentors use agitator impellers to distribute oxygen and nutrients, especially glucose (a preferred carbon/energy source).
  • Small scale fermentation refers generally to fermentation in a fermentor that is no more than approximately 100 liters in volumetric capacity, and can range from about 1 liter to about 100 liters.
  • induction of protein expression is typically initiated after the cells have been grown under suitable conditions to a desired density, e.g., an OD550 of about 180-220, at which stage the cells are in the early stationary phase.
  • a desired density e.g., an OD550 of about 180-220
  • inducers may be used, according to the vector construct employed, as is known in the art and described herein. Cells may be grown for shorter periods prior to induction. Cells are usually induced for about 12-50 hours, although longer or shorter induction time may be used.
  • various fermentation conditions may be modified.
  • additional vectors overexpressing chaperone proteins such as Dsb proteins (DsbA, DsbB, DsbC, DsbD and or DsbG) or FkpA (a peptidylprolyl cis,trans-isomerase with chaperone activity) may be used to co-transform the host prokaryotic cells.
  • the chaperone proteins have been demonstrated to facilitate the proper folding and solubility of heterologous proteins produced in bacterial host cells.
  • host strains deficient for proteolytic enzymes may be used for the present disclosure.
  • host cell strains may be modified to effect genetic mutation(s) in the genes encoding known bacterial proteases such as Protease III, OmpT, DegP, Tsp, Protease I, Protease Mi, Protease V, Protease VI and combinations thereof.
  • known bacterial proteases such as Protease III, OmpT, DegP, Tsp, Protease I, Protease Mi, Protease V, Protease VI and combinations thereof.
  • Standard protein purification methods known in the art may be employed. The following procedures are exemplary of suitable purification procedures: fractionation on immunoaffmity or ion-exchange columns, ethanol precipitation, reverse phase HPLC, chromatography on silica or on a cation -exchange resin such as DEAE, chromatofocusing, SDS-PAGE, ammonium sulfate precipitation, hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography and gel filtration using, for example, Sephadex G-75.
  • Antibody fusion proteins may be concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ® ultrafiltration unit.
  • protease inhibitors or protease inhibitor cocktails may be included in any of the foregoing steps to inhibit proteolysis of the antibody fusion proteins.
  • an antibody fusion protein may not be biologically active upon isolation.
  • Various methods for "refolding" or converting a polypeptide to its tertiary structure and generating disulfide linkages may be used to restore biological activity. Such methods include exposing the solubilized polypeptide to a pH usually above 7 and in the presence of a particular concentration of a chaotrope. The selection of chaotrope is very similar to the choices used for inclusion body solubilization, but usually the chaotrope is used at a lower concentration and is not necessarily the same as chaotropes used for the solubilization.
  • the refolding/oxidation solution will also contain a reducing agent or the reducing agent plus its oxidized form in a specific ratio to generate a particular redox potential allowing for disulfide shuffling to occur in the formation of the protein's cysteine bridge(s).
  • a reducing agent or the reducing agent plus its oxidized form in a specific ratio to generate a particular redox potential allowing for disulfide shuffling to occur in the formation of the protein's cysteine bridge(s).
  • cysteine/cystamine glutathione (GSH)/dithiobis GSH, cupric chloride, dithiothreitol(DTT)/dithiane DTT, and 2-mercaptoethanol(bME)/di-thio-b(ME).
  • GSH glutathione
  • DTT dithiothreitol
  • bME 2-mercaptoethanol
  • a cosolvent may be used to increase the efficiency of the refolding, and common reagents used for this purpose include glycerol, polyethylene glycol of various molecular weights, arginine and the like.
  • compositions comprising a K l.3 inhibitor, an antibody fusion protein and/or component of an antibody fusion protein disclosed herein.
  • the compositions may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more Kvl .3 inhibitors and/or antibody fusion proteins.
  • the Kvl .3 inhibitors and antibody fusion proteins may be different. Alternatively, they may be the same or similar.
  • the antibody fusion proteins may comprise different antibody portions, therapeutic peptides or a combination thereof.
  • compositions may further comprise one or more pharmaceutically acceptable salts, excipients or vehicles.
  • Pharmaceutically acceptable salts, excipients, or vehicles for use in the present pharmaceutical compositions include carriers, excipients, diluents, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, tonicity agents, cosolvents, wetting agents, complexing agents, buffering agents, antimicrobials, and surfactants.
  • Neutral buffered saline or saline mixed with serum albumin are exemplary appropriate carriers.
  • the pharmaceutical compositions may include antioxidants such as ascorbic acid; low molecular weight polypeptides; proteins, such as serum albumin, gelatin, or antibodies; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine;
  • suitable tonicity enhancing agents include alkali metal halides (preferably sodium or potassium chloride), mannitol, sorbitol, and the like.
  • suitable preservatives include benzalkonium chloride, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid and the like.
  • Hydrogen peroxide also may be used as preservative.
  • Suitable cosolvents include glycerin, propylene glycol, and PEG.
  • Suitable complexing agents include caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxy-propyl-beta-cyclodextrin.
  • Suitable surfactants or wetting agents include sorbitan esters, polysorbates such as polysorbate 80, tromethamine, lecithin, cholesterol, tyloxapal, and the like.
  • the buffers may be conventional buffers such as acetate, borate, citrate, phosphate, bicarbonate, or Tris-HCl.
  • Acetate buffer may be about pH 4-5.5, and Tris buffer may be about pH 7-8.5. Additional pharmaceutical agents are set forth in Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed., Mack Publishing Company, 1990.
  • the composition may be in liquid form or in a lyophilized or freeze-dried form and may include one or more lyoprotectants, excipients, surfactants, high molecular weight structural additives and or bulking agents (see, for example, U.S. Patent Nos. 6,685,940, 6,566,329, and 6,372,716).
  • a lyoprotectant is included, which is a non -reducing sugar such as sucrose, lactose or trehalose.
  • the amount of lyoprotectant generally included is such that, upon reconstitution, the resulting formulation will be isotonic, although hypertonic or slightly hypotonic formulations also may be suitable.
  • lyoprotectant concentrations for sugars e.g., sucrose, lactose, trehalose
  • a surfactant is included, such as for example, nonionic surfactants and ionic surfactants such as polysorbates (e.g., polysorbate 20, polysorbate 80); poloxamers (e.g., poloxamer 188); poly(ethylene glycol) phenyl ethers (e.g.
  • Triton sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl-or stearyl-sarcosine; linoleyl, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristamidopropyl-,
  • palmidopropyl-, or isostearamidopropyl-dimethylamine sodium methyl cocoyl-, or disodium methyl ofeyl- taurate
  • MONAQUATTM series Mona Industries, Inc., Paterson, N.J.
  • polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol e.g., Pluronics, PF68 etc.
  • Exemplary amounts of surfactant that may be present in the pre-lyophilized formulation are from about 0.001-0.5%.
  • High molecular weight structural additives may include for example, acacia, albumin, alginic acid, calcium phosphate (dibasic), cellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, dextran, dextrin, dextrates, sucrose, tylose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, disodium hydrogen phosphate, disodium phosphate, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, liquid glucose, compressible sugar, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium alginate, tragacanth microcrystalline cellulose, starch, and
  • compositions may be suitable for parenteral administration.
  • exemplary compositions are suitable for injection or infusion into an animal by any route available to the skilled worker, such as intraarticular, subcutaneous, intravenous, intramuscular, intraperitoneal, intracerebral (intraparenchymal),
  • a parenteral formulation typically will be a sterile, pyrogen-free, isotonic aqueous solution, optionally containing pharmaceutically acceptable preservatives.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringers' dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, anti -oxidants, chelating agents, inert gases and the like. See generally, Remington's
  • compositions described herein may be formulated for controlled or sustained delivery in a manner that provides local concentration of the product (e.g., bolus, depot effect) and/or increased stability or half-life in a particular local environment.
  • the compositions may comprise the formulation of antibody fusion proteins, polypeptides, nucleic acids, or vectors disclosed herein with particulate preparations of polymeric compounds such as polylactic acid, polygly colic acid, etc., as well as agents such as a biodegradable matrix, injectable microspheres, microcapsular particles, microcapsules, bioerodible particles beads, liposomes, and implantable delivery devices that provide for the controlled or sustained release of the active agent which then may be delivered as a depot injection.
  • Such sustained -or controlled-delivery means are known and a variety of polymers have been developed and used for the controlled release and delivery of drugs.
  • Such polymers are typically biodegradable and biocompatible.
  • Polymer hydrogels including those formed by complexation of enantiomeric polymer or polypeptide segments, and hydrogels with temperature or pH sensitive properties, may be desirable for providing drug depot effect because of the mild and aqueous conditions involved in trapping bioactive protein agents. See, for example, the description of controlled release porous polymeric microparticles for the delivery of pharmaceutical compositions in WO 93/15722.
  • Suitable materials for this purpose include polylactides (see, e.g., U.S. Patent No. 3,773,919), polymers of poly-(a-hydroxycarboxylic acids), such as poly-D-(-)-3-hydroxybutyric acid (EP 133,988A), copolymers of L-glutamic acid and gamma ethyl -L-glutamate (Sidman et al, Biopolymers, 22: 547-556 (1983)), poly(2-hydroxyethyl-methacrylate) (Langer et al, J. Biomed. Mater. Res., 15: 167-277 (1981), and Langer, Chem.
  • polylactides see, e.g., U.S. Patent No. 3,773,919
  • polymers of poly-(a-hydroxycarboxylic acids) such as poly-D-(-)-3-hydroxybutyric acid (EP 133,988A)
  • Sustained-release compositions also may include liposomes, which may be prepared by any of several methods known in the art (see, e.g., Eppstein et al, Proc. Natl. Acad. Sci. USA, 82: 3688-92 (1985)).
  • the carrier itself, or its degradation products, should be nontoxic in the target tissue and should not further aggravate the condition. This may be determined by routine screening in animal models of the target disorder or, if such models are unavailable, in normal animals.
  • the antibody fusion proteins disclosed herein may be microencapsulated.
  • a pharmaceutical composition disclosed herein can be administered to a subject by any suitable administration route, including but not limited to, parenteral (intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intravitreal, infusion, or local), topical, oral, or nasal administration.
  • parenteral intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intravitreal, infusion, or local
  • topical oral, or nasal administration.
  • Formulations suitable for intramuscular, subcutaneous, peritumoral, or intravenous injection can include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Formulations suitable for subcutaneous injection also contain optional additives such as preserving, wetting, emulsifying, and dispensing agents.
  • an active agent can be optionally formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • Parenteral injections optionally involve bolus injection or continuous infusion.
  • Formulations for injection are optionally presented in unit dosage form, e.g., in ampoules or in multi dose containers, with an added preservative.
  • the pharmaceutical composition described herein can be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of an active agent in water soluble form. Additionally, suspensions are optionally prepared as appropriate oily injection suspensions.
  • compositions may be administered locally via implantation into the affected area of a membrane, sponge, or other appropriate material on to which an antibody fusion protein disclosed herein has been absorbed or encapsulated.
  • the device may be implanted into any suitable tissue or organ, and delivery of an antibody fusion protein, nucleic acid, or vector disclosed herein may be directly through the device via bolus, or via continuous administration, or via catheter using continuous infusion.
  • a pharmaceutical composition comprising an antibody fusion protein disclosed herein may be formulated for inhalation, such as for example, as a dry powder.
  • Inhalation solutions also may be formulated in a liquefied propellant for aerosol delivery.
  • solutions may be nebulized.
  • Additional pharmaceutical composition for pulmonary administration include, those described, for example, in WO 94/20069, which discloses pulmonary delivery of chemically modified proteins.
  • the particle size should be suitable for delivery to the distal lung.
  • the particle size may be from 1 um to 5 um; however, larger particles may be used, for example, if each particle is fairly porous.
  • Certain formulations comprising an antibody fusion protein disclosed herein may be administered orally. Formulations administered in this fashion may be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules.
  • a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized.
  • Additional agents may be included to facilitate absorption of a selective binding agent. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders also may be employed.
  • Another preparation may involve an effective quantity of an antibody fusion protein in a mixture with non-toxic excipients which are suitable for the manufacture of tablets.
  • excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.
  • Suitable and/or preferred pharmaceutical formulations may be determined in view of the present disclosure and general knowledge of formulation technology, depending upon the intended route of administration, delivery format, and desired dosage. Regardless of the manner of administration, an effective dose may be calculated according to patient body weight, body surface area, or organ size.
  • compositions disclosed herein may be useful for providing prognostic or providing diagnostic information.
  • “Pharmaceutically acceptable” may refer to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans.
  • “Pharmaceutically acceptable salt” may refer to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • “Pharmaceutically acceptable excipient, carrier or adjuvant” may refer to an excipient, carrier or adjuvant that may be administered to a subject, together with at least one antibody of the present disclosure, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • “Pharmaceutically acceptable vehicle” may refer to a diluent, adjuvant, excipient, or carrier with which at least one antibody of the present disclosure is administered.
  • kits which comprise one or more Kvl .3 inhibitors, antibody fusion proteins or compositions thereof.
  • the Kvl .3 inhibitors and antibody fusion proteins may be packaged in a manner which facilitates their use to practice methods of the present disclosure.
  • a kit comprises a Kvl.3 inhibitor and/or antibody fusion protein described herein packaged in a container with a label affixed to the container or a package insert that describes use of the composition in practicing the method.
  • Suitable containers include, for example, bottles, vials, syringes, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the kit may comprise a container with the Kvl .3 inhibitor and/or antibody fusion protein contained therein.
  • the kit may comprise a container with an antibody portion of an antibody fusion protein and/or Kvl.3 peptide inhibitor.
  • the kit may further comprise a package insert indicating that the first and second compositions may be used to treat a particular condition.
  • the kit may further comprise a second (or third) container comprising a pharmaceutically -acceptable buffer (e.g., bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution). It may further comprise other materials desirable from a commercial and user standpoint, including, but not limited to, other buffers, diluents, filters, needles, and syringes.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline e.g., Ringer's solution and dextrose solution
  • dextrose solution e.g., bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline e.g., phosphate-buffered saline
  • Ringer's solution phosphat
  • compositions comprising the Kvl .3 inhibitor and/or antibody fusion protein may be formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to mammals, such as humans, bovines, felines, canines, and murines.
  • compositions for intravenous administration comprise solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and/or a local anaesthetics such as lignocaine to ease pain at the site of the injection.
  • the ingredients may be supplied either separately or mixed together in unit dosage form.
  • the antibody fusion protein may be supplied as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of the antibody fusion protein.
  • a hermetically sealed container such as an ampoule or sachette indicating the quantity of the antibody fusion protein.
  • the composition may be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.
  • the amount of the composition described herein which will be effective in the treatment, inhibition and/or prevention of a disease or disorder associated with aberrant expression and/or activity of a Kvl .3 peptide inhibitor may be determined by standard clinical techniques.
  • in vitro assays may optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed in the formulation may also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro, animal model test systems or clinical trials. Therapeutic Use
  • Kvl.3 inhibitors and antibody fusion proteins comprising a therapeutic Kvl .3 inhibitor peptide, for treating, alleviating, inhibiting and/or preventing one or more diseases and/or conditions.
  • the disease or condition is an autoimmune disease and/or a condition related thereto.
  • the condition is organ transplant.
  • Methods of treatment may comprise administering to a subject in need thereof a composition comprising one or more Kvl.3 inhibitor and/or antibody fusion proteins disclosed herein.
  • the Kvl .3 inhibitor and/or antibody fusion may comprise Toxin A, Toxin B, Toxin C, Toxin D, Toxin E, Toxin F, Toxin G, Toxin H, Toxin I, Toxin J, Toxin K, Toxin L, Toxin M, Toxin N, Toxin O, Toxin P, Toxin Q, Toxin R, Toxin S, Toxin T, Toxin U, Toxin V, Toxin W, Toxin X, Toxin Y, Toxin Z, Toxin AA, Toxin BB, Toxin CC, Toxin XX, and/or Shk toxin (SEQ ID NO: 131, RSCIDTIPKSRCTAFQCKHSMKYRLSFCRKTCGTC)
  • the Kvl.3 inhibitor and/or antibody fusion protein may be substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side -effects).
  • the subject may be an animal, including but not limited to animals such as cows, pigs, sheep, goats, rabbits, horses, chickens, cats, dogs, mice, etc.
  • the subject may be a mammal.
  • the subject may be a human.
  • the subject may be a non-human primate.
  • the subject may be a bovine.
  • the subject may be an avian, reptile or amphibian.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 13.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 15.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 36.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 37.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 38.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 39.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 40.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 41.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 42.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 43.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 44.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 45.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 46.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 47.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 48.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 49.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 50.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 51.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 52.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 53.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 54.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 55.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 56.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 57.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 58.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 59.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 60.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 61.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 62.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 63.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 131.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 7.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 8.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 9.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 10.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 11.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 64.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 65.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 66.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 67.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 68.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 69.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 70.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 71.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 72.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising admimstenng to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 73.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 74.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 75.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 76.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 77.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 78.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 79.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 80.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 81.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 82.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 83.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 84.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising admimstenng to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 85.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 86.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 87.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 88.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 89.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 90.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 91.
  • a method of treating an autoimmune disease or condition thereof in a subject comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 92.
  • composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 93.
  • An autoimmune disease may be a T-cell mediated autoimmune disease.
  • autoimmune diseases and conditions thereof include multiple sclerosis (MS), type 1 diabetes mellitus, rheumatoid arthritis (RA), psoriasis, lupus, Sjogren's syndrome, scleroderma, dermatomyositis, Hasmimoto's thyroiditis, Addison's disease, celiac disease, Crohn's disease, pernicious anemia, pemphigus vulgaris, vitiligo, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, myasthenia gravis, Ord's thyroiditis, Graves' disease, Guillain-Barre syndrome, acute disseminated encephalomyelitis, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatit
  • Lupus can include, but may be not limited to, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, chronic cutaneous lupus erythematosus, discoid lupus erythematosus, childhood discoid lupus erythematosus, generalized discoid lupus erythematosus, localized discoid lupus erythematosus, chilblain lupus erythematosus (hutchinson), lupus erythematosus-lichen planus overlap syndrome, lupus erythematosus panniculitis (lupus erythematosus profundus), tumid lupus erythematosus, verrucous lupus erythematosus (hypertrophic lupus erythematosus), complement deficiency syndromes, drug-induced
  • Also provided herein is a method of treating a subject prior to, during and/or after an organ transplant, the method comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 13.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 15.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 36.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 37.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 38.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 39.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 40.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 41.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an ammo acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 42.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 43.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 44.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 45.
  • compositions comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 46.
  • compositions comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 47.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 48.
  • compositions comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 49.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 50.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 51.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 52.
  • a method of treating a subject prior to, dunng and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 53.
  • compositions comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 54.
  • compositions comprising a Kvl.3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 55.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 56.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 57.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 58.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 59.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 60.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a K l .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%), 95%, or 99% identical to SEQ ID NO: 61.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 62.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 63.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising a Kvl .3 inhibitor and/or antibody fusion comprising a peptide having an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 131.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 7.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 8.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 9.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 10.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 11.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 64.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 65.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 66.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 67.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 68.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 69.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 70.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 71.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 72.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 73.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 74.
  • a method of treating a subject prior to, during and or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 75.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 76.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 77.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 78.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 79.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 80.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 81.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 82.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 83.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 84.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 85.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 86.
  • a method of treating a subject prior to, during and or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 87.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 88.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 89.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 90.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising administering to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 91.
  • a method of treating a subject prior to, during and/or after an organ transplant comprising admimstenng to the subject a composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 92.
  • composition comprising an antibody fusion comprising an amino acid sequence identical to or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to SEQ ID NO: 93.
  • Kvl .3 peptide inhibitors include those having SEQ ID NOS: 13, 15, and 36-63.
  • the method may comprise producing an antibody fusion protein disclosed herein.
  • pharmacological properties may include, but are not limited to, half-life, stability, solubility, immunogenicity, toxicity, bioavailability, absorption, liberation, distribution, metabolization, and excretion.
  • Liberation may refer to the process of releasing of a Kvl .3 peptide inhibitor from the pharmaceutical formulation.
  • Absorption may refer to the process of a substance entering the blood circulation.
  • Distribution may refer to the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolization (or
  • biotransformation, or inactivation may refer to the recognition by an organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites.
  • Excretion may refer to the removal of the substances from the body.
  • the half-life of a Kvl .3 peptide inhibitor may greater than the half-life of the non-fused Kvl .3 peptide inhibitor.
  • the half-life of the Kvl.3 peptide inhibitor may be greater than 4 hours, greater than 6 hours, greater than 12 hours, greater than 24 hours, greater than 36 hours, greater than 2 days, greater than 3 days, greater than 4 days, greater than 5 days, greater than 6 days, greater than 7 days, greater than 8 days, greater than 9 days, greater than 10 days, greater than 11 days, greater than 12 days, greater than 13 days, or greater than 14 days when administered to a subject.
  • the half-life of the Kvl.3 peptide inhibitor may be greater than 50 hours when administered to a subject.
  • the half-life of the Kvl .3 peptide inhibitor may be greater than 100 hours when administered to a subject.
  • half-life is measured within any subject and/or biological sample of a subject.
  • half-life is measured in human, mouse, rat, or other subject serum.
  • the half -life may be measured after administration of a Kvl .3 inhibitor to a subject.
  • the half-life may be measured after a Kvl .3 inhibitor is incubated in a biological sample isolated from a subject.
  • the half-life of the Kvl.3 peptide inhibitor may increase by at least about 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 or more hours.
  • the half-life of the Kvl.3 peptide inhibitor may increase by at least about 10 hours.
  • the half-life of the Kv 1.3 peptide inhibitor may increase by at least about 20 hours .
  • the half-life of the Kv 1.3 peptide inhibitor may increase by at least about 30 hours.
  • the half-life of the Kvl.3 peptide inhibitor may increase by at least about 40 hours.
  • the half-life of a Kvl.3 peptide inhibitor antibody fusion may be at least about 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200 or 300-fold greater than the half-life of the non-fused Kvl .3 peptide inhibitor.
  • the half-life of a Kvl.3 peptide inhibitor antibody fusion may be at least about 10-fold greater than the half-life of the non-fused Kvl .3 peptide inhibitor.
  • the half-life of a Kvl .3 peptide inhibitor antibody fusion may be at least about 50-fold greater than the half-life of the non-fused Kvl .3 peptide inhibitor.
  • the half-life of a Kvl.3 peptide inhibitor antibody fusion described herein may be at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, or 200% greater than the half-life of the non-fused Kvl.3 peptide inhibitor.
  • the half-life of a Kvl.3 peptide inhibitor antibody fusion described herein may be at least about 50% greater than the half-life of the non-fused Kvl.3 peptide inhibitor.
  • the activity data provided in the following examples are generally obtained using the antibodies defined in the example and exemplified by the provided SEQ ID. It is to be understood that the activities of any antibody fusion protein disclosed herein may be enhanced or attenuated depending on conditions not relating to antibody fusion protein sequence, for example, expression and purification conditions.
  • the DNA fragments encoding the heavy and light chains of palivizumab (Syn, SEQ ID NOS: 1-3), or modified palivizumab (SEQ ID NOS: 93- 100), and BVK, along with the linkers (coiled-coil or ⁇ -strand) were also synthesized by IDT and amplified by PCR
  • the fusion gene fragments were assembled by overlap extension PCR and digested with the restriction enzymes EcoRI-HF and Nhel-HF (New England Biolabs, MA), followed by DNA gel extraction.
  • the final expression vectors for the fusion antibodies were constructed by in-frame ligation of the assembled DNA into the pFuse backbone (Invivogen, CA) using T4 DNA ligase.
  • Heavy chain fusion antibodies comprise the human IgGl heavy chain constant region with mutations (E233P, L234V, L235A, AG236, A327G, A330S, P331S) to reduce complement-dependent and antibody- dependent cell -mediated cytotoxicities.
  • the expression media were harvested and sterile-filtered every 48h for twice after transfection to collect the secreted proteins.
  • the fusion antibodies were purified by Protein A chromatography (Thermo Fisher, IL) and analyzed by SDS-PAGE and mass spectrometry analysis.
  • Antibody Antibody region 1 Antibody region 2 Yield Activity (IC50) in Number FluxORTM assay
  • Toxin B was grafted into BVK scaffold to replace Ala93- Tyrl02 in CDR3H using a beta strand stalk.
  • Syn-Toxin B fusion protein was created by replacing either Gly92-Tyr93 in CDR3L or Asp56-Asp57 in CDR2H of Synagis with the Toxin B sequence connected by a coiled-coil stalk to afford Syn-Toxin B-CDR3L (SEQ ID NO: 10) or Syn-Toxin B-CDR2H (SEQ ID NO: 11), respectively (FIG. 1).
  • Synagis-Toxin B fusion antibodies (4, 5) were expressed in HEK293F cells, with a yield of 15.0 mg/L for Syn-Toxin B-CDR3L (4), and a yield of 2.5 mg/L for Syn- Toxin B-CDR2H (5).
  • SDS-PAGE analysis revealed > 90% purity. After reduction by DTT, the light chains migrated at 25-35 kDa, while the heavy chains migrated at 50-65 kDa, matching to the calculated molecular weights of peptide fused and non-fused heavy and light chains. Their identities were further confirmed by ESI-MS.
  • the increased yields of the coiled-coil fusion proteins suggest that the linker design plays a critical role in the creation of viable CDR fusions. In addition, it also appears different CDRs are able to
  • CDR3L of palivizumab was selected as a fusion site
  • CDR3H of BVK was selected as a fusion site.
  • Both antibodies were expressed in HEK293F cells with good yields (18.3 mg/L for Syn-Toxin A-CDR3L (1) and 10.7 mg/L for BVK-Toxm A-CDR3H (2)), and were characterized by SDS-PAGE and ESI-MS analysis to confirm their identities and purities.
  • Antibody fusion labeling with Alexa Fluor 488 dye To a solution of BVK-Toxin B-CDR3H (Fc null mutant, antibody 3 or Fc wild type) (0.5 mg, 3.3 nmol) in PBS buffer (500 ⁇ , pH 7.4), AF488-NHS ester (50 nmol in 5 uL DMSO, Life technology, CA) was added. The mixture was stirred at 25 °C for 2 h with shaking (50 rpm), and was purified by FPLC with a size exclusion column (Superdex 200 10/300 GL, GE Healthcare, PA).
  • the mixture can be quickly purified by excess buffer exchange with an Amicon filter (30 kDa MWCO, EMD Millipore, Ireland), or Zeba spin desalting columns (7kDa MWCO, Thermo Scientific, IL).
  • Amicon filter (30 kDa MWCO, EMD Millipore, Ireland), or Zeba spin desalting columns (7kDa MWCO, Thermo Scientific, IL).
  • the labelling extent - drug-to-antibody ratio (DAR) was characterized by ESI-Q-TOF protein mass spectrometry.
  • the overall drug -antibody ratio for both antibody fusions is about 3.5.
  • BVK-Toxin B-CDR3H (Fc-null) did not bind to THP-1 at concentrations up to 100 nM, while BVK-Toxin B-CDR3H with regular Fc bound significantly to THP-1 at concentrations as low as 1 nM.
  • Example 2 In vitro activities of Kvl.3 inhibitor antibody fusion proteins
  • T cells activated by anti-CD3 are widely used to evaluate the effect of Kvl .3 blockade by peptide inhibitors.
  • Effector memory T cells can be selectively activated by aCD3 -mediated T cell receptor (TCR) signaling independent of co-stimulation, while the full activation of naive and central memory T cells requires costimulatory signals provided by CD28 and/or other protein members.
  • TCR T cell receptor
  • TCR T cell receptor
  • the Toxin A fusion antibodies are more potent than Toxin B-fusions in inhibiting human T cell activation (Table 2, part B).
  • Viability assays confirmed that the suppression of T cell activation by Toxin A fusion antibodies was not due to cytotoxicity. Taken together, these results demonstrate excellent tolerance of selected CDRs to substitution by disulfide-bond rich peptides.
  • Flow cytometry analysis For surface antigen-expression analysis, the following fluorophore- conjugated anti-human antibodies were used: aCD3-PB (UCHT1, BioLegend, CA), aCD69-PE (FN50, BioLegend, CA), aCD25-APC/Cy7 (M-A251, BioLegend, CA), aCD45RA-PB (HI100, BioLegend, CA), aCCR7-Alexa Fluor 647 (3D12, BD Pharmingen, CA).
  • aCD3-PB UCHT1, BioLegend, CA
  • aCD69-PE FN50, BioLegend, CA
  • M-A251, BioLegend, CA aCD45RA-PB
  • aCCR7-Alexa Fluor 647 3D12, BD Pharmingen, CA.
  • Human T cells or T EM cells were stained with these antibodies in Hanks' balanced salt solution (Mediatech, VA)/2% FBS for 60 min at 4 °C, after which they were washed twice with the same medium and analyzed on LSR II flow cytometer equipped with a high throughput sampler (BD Bioscience, CA).
  • human TruStain FcX BioLegend, CA was added and incubated with cells for 20 minutes prior to staining with other antibodies of interest. All the results were processed with FlowJo software (FlowJo, OR).
  • Human T cell activation Human T cell activation was performed based on published procedures. Briefly, T cells were isolated from freshly purified peripheral blood mononuclear cells (PBMCs) using a T cell negative enrichment kit (Stem cell technologies, Canada). The purity was > 95% based on CD3 -positive signals monitored by flow cytometry. The freshly isolated T cells were suspended in RPMI media (with 10% FBS, 100 IU/mL penicillin, and 100 ⁇ g/mL streptomycin) and plated at 1.5 x 10 5 cells per well in flat- bottomed, 96-well plates. Proteins and peptides were serially diluted in PBS as 10X stock, and added in triplicate to T cells, respectively.
  • PBMCs peripheral blood mononuclear cells
  • T cell antigen marker CD25 was analyzed by flow cytometry using the procedure described above. With another separate set of samples, T cell antigen marker CD69 was analyzed approximately 24 h after stimulation.
  • T cells For proliferation assay, purified T cells were labelled with 2 ⁇ CFSE (Thermo Fisher, IL) based on manufacturer's instructions, before incubation with peptide/protein samples and activation by aCD3. The mixtures were incubated for six days, followed by washing with HBSS/2% FBS and flow cytometry analysis on FITC channel.
  • CFSE Thermo Fisher, IL
  • Cell cytotoxicity Cell viabilities were measured by quantifying ATP content with CellTiter Glo (Promega, WI) for which the luminescence was detected on a Gemini EM microplate reader (Molecular Devices, CA). Viability of unstimulated T cells was used as a control and defined as 100%.
  • Antibody Kvl.3 inhibitor CD69 ECso CD25 ECso TNFa ECso Proliferation
  • Example 2 The experiments of Example 2 are repeated using antibody fusion proteins selected from antibody numbers: 6- 33 (Table 1).
  • CDR7 T EM cells were isolated from human peripheral blood T cells by removing the CCR7 + naive and central memory T cells with biotinylated anti-CCR7 antibody using anti-biotin magnetic beads. The T EM cell fraction was confirmed by flow cytometry to be 97.5% CCR7-and 99.7% CD3+.
  • Toxin A peptide and Toxin A antibody fusions are highly selective against T EM cells, which is likely due to high selectivity for Kvl.3 over KCa3.1 (>1500 fold for Toxin A) (Table 3).
  • Toxin B peptide and Toxin B antibody fusions lacked potency and selectivity against T EM .
  • Human T F M cell activation assay Human T EM cells were isolated following general published procedures. Briefly, purified T cells were suspended at a concentration of 10 7 cells per RoboSep buffer (Stem cell technologies, Canada) and incubated with a biotinylated anti-CCR7 antibody (3D 12, BD PharMingen, CA) at a ratio of 20 ⁇ . antibody per one million cells. The mixture was incubated at room temperature for 15 minutes, followed by washing with at least 2 mL buffer per 10 7 cells.
  • a biotinylated anti-CCR7 antibody 3D 12, BD PharMingen, CA
  • the labelled cells were re-suspended in RoboSep buffer, and mixed with anti-biotin MicroBeads (Miltenyi Biotec, CA) at a ratio of 20 uL antibody per ten million cells. The mixture was incubated at room temperature for 10 min, washed once, re-suspended in 500 buffer and loaded onto the LD column (Miltenyi Biotec, CA) for a negative selection aided by Magnet. The eluted cells were pure CCR7 TEM, which were then seeded at 50k cells per well, treated, activated and characterized using the aforementioned procedures described for human T cell activation.
  • Example 3 The experiments of Example 3 are repeated using antibody fusion proteins selected from antibody numbers: 6- 33 (Table 1).
  • Syn-Toxin A-CDR3L (1) The stability of Syn-Toxin A-CDR3L (1) fusion was examined in freshly-collected rat serum for up to 72 h.
  • the amount of Syn-Toxin A-CDR3L was determined by ELISA based on quantitation of Toxin A fusion that is able to bind Kvl .3. 52% of the Toxin A peptide remained after 72 hours of incubation, while 84% of Syn-Toxin A-CDR3L (1) remained at 72 hours.
  • PK pharmacokinetic analysis of Syn-Toxin A-CDR3L (1) was performed in rats. Plasma samples were analyzed using the same ELISA method described above.
  • Syn-Toxin A-CDR3L (1) had a long half-life, with estimated terminal half -lives of 54.0 h for intravenous injection (FIG. 2B) and 38.4 h for subcutaneous injection (FIG. 2A), which is much longer than shk-186 (less than 10 min in rats), the most advanced Kvl.3 inhibitor in development.
  • Rat serum Eppendorf tubes containing 0.15 mg/mL antibody fusion per tube was each added 100 ⁇ ⁇ fresh rat serum. The tubes were incubated at 37 °C for different time (Oh, 6h, 24h, 48h, and 72h), immediately frozen in liquid nitrogen, and stored at -80 °C until further processing. After thawing on ice, all the samples were purified by Protein A chromatography to extract IgGs. The amount of the antibody fusion in each sample extract was determined by cell -based Kvl .3 binding sandwich ELISA.
  • Kvl .3-overexpressing CHO cells (Charles River, MA) were cultured on a flat-bottom 96-well plate (black) over night to allow for attachment (20k/well). After washing with PBS buffer, cells were fixed onto the bottom of wells by spinning down and incubating in 8% paraformaldehyde for 15 minutes. The rest of ELISA procedures were the same as those published by Abeam (ICE, abl 11542). For the final steps, HRP -labeled anti-human IgG(Fc) antibody (ELITechGroup, Netherlands) was diluted 1/1000 in blocking buffer (PBS/ 5%BSA/ 0.1% Tween), and applied for 1 h followed by extensive washing.
  • blocking buffer PBS/ 5%BSA/ 0.1% Tween
  • QuantaBlu fluorogenic ELISA substrate (Thermo Fisher, IL) was then added and fluorescence signals were obtained by reading through a Spectramax plate reader. The amount of the anti-Kvl .3 fusion antibody was quantified by extrapolating the signal into the linear range of a standard curve (signal vs concentration).
  • signal vs concentration For peptide, each eppendorf tube contains 1 nmole peptide mixed with 100 fresh rat serum, and was processed the same way as described above for antibody samples. Fifty microliters of the samples after incubating with serum was mixed with 200 of 0.01% TFA in 50% water/50% acetonitrile with 5 ng/mL benztropine as an internal standard.
  • the mixture was vortexed for 15 sec and placed at 4°C for 10 min.
  • the sample mixture was centrifuged at 13,300 rpm for 15 min to pellet the precipitated proteins.
  • 150 of the supernatant was diluted with 100 ⁇ ⁇ of 0.01% TFA in water.
  • Samples were then analyzed by LC/MS using an Agilent Technologies (Santa Clara, CA) 1100 HPLC system mated to an AB Sciex (Redwood City, CA) 4000 Q Trap.
  • a Phenomenex (Torrence, CA) Kinetix Evo C18, 5.0 ⁇ , 100-A, 2.1 x 50-mm column was used for separation.
  • Example 4 After thawing and proper dilution of plasma sample, the amount of antibody in each blood sample was quantified by the aforementioned anti-Kvl.3 sandwich ELISA. Data was analyzed by the PK modeling program (WinNonlin, Certara, NJ) to determine the pharmacokinetic parameters. [00189] The experiments of Example 4 are repeated using antibody fusion proteins selected from antibody numbers: 6-33 (Table 1).
  • Syn-Toxin A-CDR3L (1) was evaluated in vivo for its effectiveness in suppressing delayed type hypersensitivity (DTH) in rats, a response that is regulated mainly by the homing of CD4+ effector memory T cells.
  • Lewis rats were immunized with ovalbumin on the first day, and then challenged again with ovalbumin injection into the left ear after a week of sensitization. The challenged ear was swollen, and ear thickness was measured after 24 h as an indication of the immune response against ovalbumin. Since Syn-Toxin A-CDR3L reached Cmax at ⁇ 24hrs, it was s.c.
  • Toxin A peptide also showed activity in this experiment, although to a lesser extent (15% reduction of ⁇ ear thickness with one dose, 27% reduction with two doses).
  • the in vivo activity of Syn-Toxin A-CDR3L is close to that of the parent shk peptide (34% reduction of ⁇ ear thickness with one dose and 43% reduction with two doses).
  • Future in vivo studies using different dosing frequencies and dosages may be performed to further elucidate the PK/PD relationship of Syn-Toxin A-CDR3L.
  • Syn-Toxin A-CDR3L was only dosed once on day 6 at 5 mg/kg.
  • peptide SHK or Toxin A was injected s.c. at a single dosage of 100 ⁇ g/kg/day, respectively.
  • SHK or Toxin A was also dosed only once on day 7 at 100 ug/kg.
  • PBS was used as vehicle control for all the treatment groups. On day 7, all groups were challenged by injection of 20 (1 mg/mL) ovalbumin into the pinna of left ear and PBS into the other ear. The only exception was "sham" group, with both ears injected with PBS.
  • Ear swelling was measured Oh, 24 h, and 48 h after the challenge with Mitutoyo QUICK Mini caliper. Values given in the Figure are the difference in the thickness (mm) between the ovalbumin -challenged left ear and the PBS- injected right ear at the time 24h after challenge.
  • Example 5 The experiments of Example 5 are repeated using antibody fusion proteins selected from antibody numbers: 6-33 (Table 1). [00193] The experiments described in Examples 1-5 indicate the versatility of the antibody-CDR loop fusion strategy by generating a specific antibody inhibitor of the human Kvl .3 channel. Fusion of toxins into CDR3L of Synagis via a coiled -coil linker exhibited superior activity to other fusions. The antibody-toxin fusion showed excellent in vitro potency and selectivity in assays with human T EM cells. Syn-Toxin A- CDR3L also significantly suppressed DTH reactions in vivo in rats. Future studies include evaluating the antibody toxin fusion in disease models for the prevention and treatment of autoimmune diseases such as multiple sclerosis, Type 1 diabetes and psoriasis.
  • autoimmune diseases such as multiple sclerosis, Type 1 diabetes and psoriasis.
  • Example 6 In vitro potassium ion channel assay
  • Example 1 The activity of antibodies generated in Example 1 were assayed for potassium ion channel activity using an FluxORTM assay. The resulting IC50 data is shown in Table 1.
  • Kvl.3 inhibitor peptides and Kvl.3 inhibitor antibodies comprising toxins A-Z, XX, AA-CC are tested for binding to different channels.
  • the Kvl.3 inhibitor molecules will be tested with CHO cell lines selectively expressing channels, such as Kvl l. l (hERG), Kvl . l/ Kvl .2, Kvl .5, KCa3.1, Kvl .3, Navl .5, and Cavl .2, in a patch clamp assay.
  • Kvl .3 inhibitor molecules identified that bind to the channels are tested in an in vitro assay, such as generally described in Examples 2 and 3.
  • palivizumab H5 100 SCSVMHEALHNHYTQKSLSLSPGK
  • Toxin A LC VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH fusion 65 KVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin C LC KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK fusion 66 HKVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin E LC KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK fusion 68 HKVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin F LC LLrYDTSKLASGVPSRFSGSGSGTAFTLTISSLQPDDFATYYCFQG fusion 69 NGGSGAKLAALKAKLAALKGGGGSAGAISCVGSPECPPKCRAQG l iihk- 6. l usioti protein se uences
  • Toxin G LC VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH fusion 70 KVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin H LC KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK fusion 71 HKVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin I LC VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH fusion 72 KVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin K LC LLIYDTSKLASGVPSRFSGSGSGTAFTLTISSLQPDDFATYYCFQG fusion 74 NGGSGAKLAALKAKLAALKGGGGSAAAISAVGSPECPPKCRAQG l iihk- 6. l usioti protein se uences
  • Toxin L LC KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK fusion 75 HKVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin M LC KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK fusion 76 HKVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin 0 LC KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK fusion 78 HKVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin Q LC KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK fusion 80 HKVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin R LC KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK fusion 81 HKVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin S LC WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV fusion 82 YACEVTHQGLSSPVTKSFNRGEC
  • Toxin T LC WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV fusion 83 YACEVTHQGLSSPVTKSFNRGEC
  • Toxin AA LC VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH fusion 90 KVYACEVTHQGLSSPVTKSFNRGEC
  • Toxin CC LC EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY fusion 92 EKHKVYACEVTHQGLSSPVTKSFNRGEC
  • Each of XI -XI 1 and Z1-Z8 may be any natural or unnatural amino acid, or may indicate absence of an amino acid.
  • XI is S or K
  • X2 is S or P
  • X3 is P or K
  • X4 is P or L
  • X5 is K or P
  • X6 is Pv or G
  • X7 is T or indicates no amino acid present at this position
  • X8 is K or P
  • X9 is N or Y
  • X10 is Y or N
  • X I 1 is Y, R, F or G
  • Zl is C, A, G, S, I, or L
  • Z2 is C, A, G, S, I, or L
  • Z3 is C, A, G, S, I, or L
  • Z4 is C, A, G, S, I, or L
  • Z5 is C, A, G, S, I, or L
  • Z6 is C, A, G, S, I, or L
  • Toxin Z 60 AAAISCVGSPECPPKCRAQGCKNGKCMNRKCKCNYC
  • Z8 is C, A, G, S, I, or L.
  • a composition comprising a peptide inhibitor of a voltage-gated channel positioned within, or replacing one or more amino acids of, a first CDR of an antibody variable domain; wherein the first CDR, a second CDR, and a third CDR of the antibody variable domain do not form a binding site specific for a human antigen.
  • composition of embodiment 1, wherein the first CDR is a CDR3 of a palivizumab light chain.
  • the composition of embodiment 1, wherein the first CDR comprises an amino acid sequence at least about 90% identical to a sequence selected from SEQ ID NOS: 26 and 117-123.
  • the composition of any of embodiments 1-3, wherein the second CDR comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 24 or 115.
  • composition of embodiment 1, wherein the first CDR is a CDR2 of a palivizumab light chain.
  • the composition of embodiment 1, wherein the first CDR is a CDR1 of a palivizumab light chain.
  • the composition of embodiment 1, wherein the first CDR is a CDR3 of a palivizumab heavy chain.
  • the composition of embodiment 1, wherein the first CDR is a CDR2 of a palivizumab heavy chain.
  • the composition of embodiment 1, wherein the first CDR is a CDR1 of a palivizumab heavy chain.
  • composition of embodiment 11, wherein the antibody Fc region comprises one or more mutations to reduce antibody-dependent cellular cytotoxicity (ADCC).
  • ADCC antibody-dependent cellular cytotoxicity
  • composition of embodiment 11, wherein the antibody Fc region comprises an amino acid sequence at least about 90% identical to the Fc region of SEQ ID NO: 3 or 124.
  • composition of any of embodiments 15-17, wherein the first extension peptide comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 16.
  • composition of any of embodiments 15-18, wherein the second extension peptide comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 17.
  • composition of embodiment 20, wherein the peptide linker comprises no regular secondary structure.
  • composition of embodiment 20 or embodiment 21, wherein at least about 50% of the amino acids of the peptide linker are glycine and/or serine.
  • composition of any of embodiments 1-23, wherein the peptide inhibitor of the voltage -gated channel is a peptide inhibitor of Kv 1.1, Kvl .2, Kvl .3, Kvl .4, Kvl .5, Kvl.6, Kvl.7, Kv2.1 , Kv3.1 , Kv3.2, Kvl l. l , Kcl. l , Kc2.1 , Kc3.1 , Navl .2, Navl.4, and Cavl.2, or any combination thereof .
  • the composition of embodiment 26, wherein the peptide inhibitor of the voltage-gated channel is a peptide inhibitor of Kvl .3.
  • composition of any of embodiments 1-27, wherein the peptide inhibitor of the voltage-gated channel comprises four or more cysteine amino acids.
  • composition of any of embodiments 1-27, wherein the peptide inhibitor of the voltage-gated channel comprises Toxin A.
  • composition of any of embodiments 1-27, wherein the peptide inhibitor of the voltage-gated channel comprises the amino acid sequence of SEQ ID NO: 36.
  • composition of any of embodiments 1-27, wherein the peptide inhibitor of the voltage-gated channel comprises Toxin B.
  • composition of any of embodiments 1-27, wherein the peptide inhibitor of the voltage-gated channel comprises an amino acid sequence at least about 90% identical to a sequence selected from SEQ ID NOS: 13, 15, and 37-63.
  • a method of treating an individual for an autoimmune disease or condition thereof comprising administering to the individual an effective amount of the composition of any of embodiments 1-32.
  • a composition comprising a peptide inhibitor of a voltage-gated channel positioned within, or replacing one or more ammo acids of, a first CDR of an antibody variable domain; wherein the antibody variable domain further comprises a second CDR and a third CDR of an anti-lysozyme antibody.
  • composition of embodiment 36, wherein the first CDR comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 29.
  • composition of any of embodiments 36-38, wherein the second CDR comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 27.
  • composition of any of embodiments 36-39, wherein the third CDR comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 28.
  • composition of embodiment 36 wherein the first CDR is a CDR1 of a heavy chain of the anti- lysozyme antibody.
  • composition of any of embodiments 36-45, further comprising an antibody Fc region comprising an antibody Fc region.
  • composition of embodiment 46 wherein the antibody Fc region comprises one or more mutations to reduce antibody-dependent cellular cytotoxicity (ADCC).
  • ADCC antibody-dependent cellular cytotoxicity
  • composition of embodiment 46, wherein the antibody Fc region comprises an amino acid sequence at least about 90% identical to the Fc region of SEQ ID NO: 3.
  • composition of any of embodiments 50-52, wherein the first extension peptide comprises an ammo acid sequence at least about 90% identical to SEQ ID NO: 18.
  • composition of embodiment 55, wherein the peptide linker comprises no regular secondary structure.
  • composition of embodiment 55 or embodiment 56, wherein at least about 50% of the amino acids of the peptide linker are glycine and/or serine.
  • composition of embodiment 59, wherein the cation channel is a potassium channel.
  • the composition of any of embodiments 36-58, wherein the peptide inhibitor of the voltage-gated channel is a peptide inhibitor of Kv 1.1 , Kvl.2, Kvl.3, Kvl.4, Kvl.5, Kvl .6, Kvl .7, Kv2.1 , Kv3.1 , Kv3.2, Kvl l. l , Kcl. l , Kc2.1 , Kc3.1 , Navl .2, Navl.4, and Cavl.2, or any combination thereof .
  • the composition of embodiment 61, wherein the peptide inhibitor of the voltage-gated channel is a peptide inhibitor of Kvl .3.
  • composition of any of embodiments 36-62, wherein the peptide inhibitor of the voltage-gated channel comprises four or more cysteine amino acids.
  • composition of any of embodiments 36-62, wherein the peptide inhibitor of the voltage-gated channel comprises Toxin A.
  • composition of any of embodiments 36-62, wherein the peptide inhibitor of the voltage-gated channel comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 13.
  • composition of any of embodiments 36-62, wherein the peptide inhibitor of the voltage-gated channel comprises Toxin B.
  • composition of any of embodiments 36-62, wherein the peptide inhibitor of the voltage-gated channel comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 15.
  • a method of treating an individual for an autoimmune disease or condition thereof comprising administering to the individual an effective amount of the composition of any of embodiments 36-67.
  • a method of treating an autoimmune disease in an individual in need thereof comprising administering to the individual an effective amount of a peptide inhibitor of a voltage-gated channel; wherein the peptide inhibitor of the voltage-gated channel is present in an insert portion of a modified variable domain of an antibody, the insert portion positioned within or replacing one or more amino acids of a first CDR of the variable domain.
  • the voltage-gated channel is a cation channel selected from a potassium, sodium and calcium channel.
  • the peptide inhibitor of the voltage-gated channel is a peptide inhibitor of Kvl.1 , Kvl .2, Kvl.3, Kvl.4, Kvl.5, Kvl.6, Kvl .7, Kv2.1 , Kv3.1 , Kv3.2, Kvl l . l , Kcl . l , Kc2.1 , Kc3.1 , Navl.2, Navl .4, and Cavl .2, or any combination thereof.
  • the method of embodiment 71, wherein the peptide inhibitor of the voltage-gated channel is Toxin A.
  • the method of embodiment 71, wherein the peptide inhibitor of the voltage-gated channel comprises the amino acid sequence of SEQ ID NO: 36. 79.
  • the method of embodiment 71, wherein the peptide inhibitor of the voltage-gated channel is Toxin B.
  • peptide inhibitor of the voltage-gated channel comprises an amino acid sequence at least about 90% identical to a sequence selected from SEQ ID NOS: 13, 15, and 37-63.
  • extension peptide and second extension peptide.
  • the insert portion comprises: the first extension peptide, a first linker, the peptide inhibitor of the voltage-gated channel, a second linker, and the second extension peptide.
  • modified variable domain further comprises a second CDR and a third CDR.
  • second CDR comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 24 or 1 15.
  • modified variable domain further comprises a second CDR and a third CDR.
  • the antibody Fc region comprises one or more mutations to reduce antibody -dependent cellular cytotoxicity (ADCC).
  • ADCC antibody -dependent cellular cytotoxicity
  • the method of any of embodiments 71-115, wherein the autoimmune disease is multiple sclerosis.
  • the method of any of embodiments 71-115, wherein the autoimmune disease is psoriasis.
  • a method of inhibiting the function or activation of an effector memory T (T EM ) cell comprising contacting the T EM cell with a therapeutic peptide having an amino acid sequence at least about 90% identical to SEQ ID NO: 13, 36 or 15; wherein the therapeutic peptide is present in a variable domain of an antibody modified with an insert portion positioned within, or replacing one or more amino acids of, a first CDR of the variable domain; wherein the insert portion comprises the therapeutic peptide.
  • the therapeutic peptide comprises an amino acid sequence at least about 90% identical to a sequence selected from SEQ ID NOS: 37-63.
  • the method of embodiment 1 18, wherein the therapeutic peptide is Toxin A or a mutant thereof.
  • the method of embodiment 1 18, wherein the therapeutic peptide is Toxin B or a mutant thereof.
  • the method of any of embodiments 118-122, wherein contacting the T EM cell with the therapeutic peptide comprises administering to an individual an effective amount of the therapeutic peptide.
  • the method of embodiment 123, wherein the individual is a recipient of an organ transplant.
  • the insert portion comprises: the first extension peptide, the therapeutic peptide, and the second extension peptide.
  • variable domain is a variable domain of palivizumab.
  • sequence at least about 90% identical to a sequence selected from SEQ ID NOS: 26 and 117-123.
  • variable domain is a variable domain of an anti-lysozyme antibody.
  • a method of manufacturing an inhibitor of a voltage -gated channel having improved half-life in a biological sample comprising: (a) providing an expression vector comprising a nucleic acid sequence encoding for a polypeptide comprising a therapeutic peptide having inhibitory activity against the voltage gated-channel, wherein the therapeutic peptide is present in a variable domain of an antibody modified to comprise an insert portion, the insert portion positioned within or replacing one or more amino acids of a first CDR of the variable domain; wherein the insert portion comprises the therapeutic peptide; (b) expressing the polypeptide from a cell culture; and (c) purifying the polypeptide to obtain the inhibitor of the voltage gated-channel, the inhibitor of the voltage gated- channel having a greater half-life in the biological sample than the therapeutic peptide.
  • the voltage-gated channel is a cation channel selected from a potassium, sodium and calcium channel.
  • the inhibitor of the voltage-gated channel is a peptide inhibitor of Kv 1.1 , Kvl .2, Kvl .3, Kvl .4, Kvl .5, Kvl.6, Kvl.7, Kv2.1 , Kv3.1 , Kv3.2, Kvl l. l , Kcl . l , Kc2.1 , Kc3.1 , Navl .2, Navl .4, and Cavl.2, or any combination thereof .
  • the therapeutic peptide comprises an amino acid sequence at least about 90% identical to a sequence selected from SEQ ID NOS: 13, 15, and 37- 63.
  • the insert portion comprises: the first extension peptide, a first linker, the therapeutic peptide, a second linker, and the second extension peptide.
  • variable domain is a variable domain of palivizumab.
  • sequence at least about 90% identical to a sequence selected from SEQ ID NOS: 26 and 117-123.
  • variable domain is a variable domain of an anti-lysozyme antibody.
  • a composition comprising a peptide inhibitor of a voltage-gated channel positioned within, or replacing one or more amino acids of, a first CDR of an antibody light chain variable domain.
  • composition of embodiment 197, wherein the antibody light chain variable domain is a
  • palivizumab light chain variable domain.
  • composition of any of embodiments 197-200, wherein the antibody light chain variable domain comprises a second CDR comprising an amino acid sequence at least about 90% identical to SEQ ID NO: 24 or 115.
  • composition of any of embodiments 197-201, wherein the antibody light chain variable domain comprises a third CDR comprising an amino acid sequence at least about 90% identical to SEQ ID NO: 25 or 116.
  • composition of any of embodiments 197-207, further comprising an antibody Fc region is 208.
  • composition of embodiment 208, wherein the antibody Fc region comprises one or more
  • composition of embodiment 209, wherein the antibody Fc region comprises an amino acid sequence at least about 90% identical to the Fc region of SEQ ID NO: 3 or 124.

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Abstract

L'invention concerne des peptides inhibiteurs du canal Kv1.3 et des compositions comprenant un inhibiteur Kv1.3 peptidique relié à une séquence d'anticorps. Ces molécules peuvent être utiles pour le traitement de maladies et d'états pathologiques médiés par les lymphocytes T tels que les maladies auto-immunes.
PCT/US2017/041376 2016-07-11 2017-07-10 Peptides bloquant le canal kv1.3 et utilisations de ces derniers Ceased WO2018013483A1 (fr)

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EP3387019A4 (fr) * 2015-12-09 2019-04-17 The California Institute for Biomedical Research Protéines de fusion d'immunoglobuline de relaxine et procédés d'utilisation
WO2025133137A1 (fr) * 2023-12-21 2025-06-26 SelectION Therapeutics GmbH Peptide pour le traitement du psoriasis vulgaire ou de l'arthrite psoriasique

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JP2017515502A (ja) * 2014-05-08 2017-06-15 コノジェネティックス バイオサイエンシズ ゲーエムベーハー Ｋｖ１．３カリウムチャネルアンタゴニスト
US20190375795A1 (en) * 2014-05-08 2019-12-12 Cgtx-Peptide Development Gmbh Kv1.3 potassium channel antagonists
US10800815B2 (en) * 2014-05-08 2020-10-13 Select ION Therapeutics GMBH Kv1.3 potassium channel antagonists
AU2019240693B2 (en) * 2014-05-08 2020-10-15 SelectION Therapeutics GmbH Kv1.3 potassium channel antagonists
EP3387019A4 (fr) * 2015-12-09 2019-04-17 The California Institute for Biomedical Research Protéines de fusion d'immunoglobuline de relaxine et procédés d'utilisation
US11161891B2 (en) 2015-12-09 2021-11-02 The Scripps Research Institute Relaxin immunoglobulin fusion proteins and methods of use
EP4011919A3 (fr) * 2015-12-09 2022-10-12 The Scripps Research Institute Protéines de fusion d'immunoglobuline de relaxine et procédés d'utilisation
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WO2025133137A1 (fr) * 2023-12-21 2025-06-26 SelectION Therapeutics GmbH Peptide pour le traitement du psoriasis vulgaire ou de l'arthrite psoriasique

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